Nickel-Catalyzed Reductive Coupling Reactions of 1,6-Enynes and the Total
Synthesis of (+)-Acutiphycin
by
Ryan Thomas McLeod Moslin
B.Sc. Honours Chemistry
University of British Columbia, 2001
Submitted to the Department of Chemistry
in Partial Fulfillment of the Requirements
for the Degree of
DOCTOR OF PHILOSOPHY
IN ORGANIC CHEMISTRY
at the
Massachusetts Institute of Technology
December 2006
C 2007 Massachusetts Institute of Technology
All rights reserved
Signature of Author
Sigatue
o
Auhor-
4X-
C-<
Department of Chemistry
December 19,
2006
.(N
Certified by
Timothy F. Jamison
Associate Professor of Chemistry
Thesis Supervisor
Accepted by
,1 -
Robert
ii: W. Field
Chairman, Department Committee on Graduate Students
MASSACHUSETTS INSTITUTE
OF TECHNOLOGY
MAR 0 3 2007
LIBRARIES
---
AKCUHIVE
This doctoral thesis has been examined by a committee in the Department of Chemistry as
follows:
\
Professor Rick L. Danheiser
Chairman
N~l
Professor Timothy F. Jamison
(J
Professor Stephen L. Buchwald
.
Thesis Supervisor
To Mom and Dad, Mairen, Ian and Karen
Nickel-Catalyzed Reductive Coupling Reactions of 1,6-Enynes and the Total Synthesis of
(+)-Acutiphycin
by
Ryan Thomas McLeod Moslin
Submitted to the Department of Chemistry on December 19, 2006
in Partial Fulfillment of the Requirements for the Degree of
Doctor of Philosophy in Organic Chemistry
ABSTRACT
Nickel-Catalyzed Reductive Coupling Reactions of Aldehydes and Chiral 1,6-Enynes
A study of nickel-catalyzed reductive coupling reactions of aldehydes and chiral 1,6-enynes
has provided evidence for stereospecific ligand substitution from a planar three-coordinate nickel
species as a plausible explanation of regioselectivity in the nickel-catalyzed reductive coupling
of aldehydes and 1,6-enynes. In the absence of a phosphine additive, high regioselectivity and
high diastereoselectivity are obtained as a direct result of coordination of both the alkyne and the
olefin to the metal center during the C-C bond-forming step.
i-PrCHO
Ni(cod) 2
Et3B
OH
Me
R
Me
regioselectivity
dr
>95: 5 A: B
95: 5
5:>95 A:B
-1:1
Me
+
EtMe
Et
Ni(cod) 2
Et3B
PCyp3
OH
R
Me
B
Me
Me
Total Synthesis of (+)-Acutiphycin
Synthetic studies toward the total synthesis of (+)-acutiphycin led to, and were in turn further
developed by, the study of nickel-catalyzed reductive coupling reactions of 1,6-enynes and
aldehydes.
0
0
,TBDPS
OH
,\Me
x 'Y /Me
M
O
OTBDPS
CHO
MeO t"ý
Ni(cod) 2
(cat.)
Et3B
O
Me Me Me
no 5hosphine additive
>9 5:5 regioselectivity
,TBDPS
O
OH
MeO
,\\Me
S= OTBS; Y = H
62:38 dr
'OTBS
Ultimately, though not employing the nickel-catalyzed reaction, a highly convergent total
synthesis of (+)-acutiphycin featuring an intermolecular SmI2-mediated Reformatsky coupling
reaction and macrolactonization initiated by a retro-ene reaction of an alkoxyalkyne was
developed. The resulting synthesis was 18 steps in the longest linear sequence from either
methyl acetoacetate or isobutyraldehyde.
OTBDPS
OTBDPS
CH2 =CH 2
,\Me
O OH H
A
"OH
n-Bu
Me
12 steps (LLS)
from commercial compounds
Thesis Supervisor: Timothy F. Jamison
Title: Associate Professor of Chemistry.
Me
90% yield
5 steps to (+)-acutiphycin
PREFACE
Portions of this thesis have appeard in the following articles that were co-written by the author,
and are reproduced in part with permission from:
Mechanistic Implications of Nickel-Catalyzed Reductive Coupling of Aldehydes and Chiral
1,6-Enynes. Moslin, Ryan M.; Jamison, Timothy F. Org. Lett. 2006, 8, 455-458.
Copyright 2006 American Chemical Society.
Directing Effects of Tethered Alkenes in Nickel-Catalyzed Couplings of 1,6-Enynes and
Aldehydes. Moslin, Ryan M.; Miller, Karen M.; Jamison, Timothy F. Tetrahedron 2006,
62, 7598-7610. Copyright 2006 Elsevier Science.
Highly Convergent Total Synthesis of (+)-Acutiphycin. Moslin, Ryan M.; Jamison, Timothy
F. J. Am. Chem. Soc. 2006, 128, 15106-15107. Copyright 2006 American Chemical
Society.
Total Synthesis of (+)-Acutiphycin: Discovery of Regioselective Nickel-Catalyzed Reductive
Coupling Reactions Directed by a Remote Alkene. Moslin, Ryan M.; Jamison,
Timothy F. manuscriptsubmitted for publication.
ACKNOWLEDGMENTS
I never really thought that I'd get to this point, but I know that I have gotten here because of
the people who have supported and believed in me throughout my life. I'd like to use this as an
opportunity to thank them.
I've never been an easy person to work with, or to be around, but I'm damn near impossible to
teach, which is why I must thank each and everyone who has undertaken this difficult task. I'd
especially like to thank Mr. Farnworth who brought patience and humour to every class, and
installed a life-long love of mathematics in all of those he taught. Mr. Farnworth always had
time outside of class for his students, he even taught those who had already graduated from high
school only to realize they really did need math in the real world! Thanks for the lunchtime
chess games, they meant a lot to me.
I'd also like to thank Professor Michael Gerry for teaching me that quantum mechanics and
physical chemistry are for everyone, even those arrogant enough to proclaim "I don't need to
know this, I'm an organic chemist". I've never enjoyed a class or a subject more than Chem.
420, and I deeply hope that one day I can once again consider myself a physical chemist.
In my second year at UBC I struggled to find something that I could see myself doing for the
rest of my life. I enjoyed mathematics but knew that I could never be an elite mathematician. I
had the incredible good fortune of having Professor Edward Piers for my first to organic
chemistry courses. Over the course of a year Professor Piers opened my eyes to the beauty of
organic synthesis. A spectacular combination of imagination and deduction, I've been in love
with the field ever since.
To the entire Science One faculty: I'm sorry that you had to see me at my lowest point, thank
you for helping me get out of it.
To Professors Chris Orvig and Gregory Dake, thank you for providing me a wonderful
working environment in which to learn, thanks also to Dave, Michael and Denise who first
taught me how to work in an academic lab.
To my lab mates, you've all been wonderful over the years and I wish you all the best.
Working with Dr. Aaron Skaggs was an honour, and I would do so again in a heartbeat. The
brilliance of my year mate Dr. Chudi Ndubaku pushed me to be a better chemist, and more
importantly Chudi was a good friend who cared deeply for those around him. Andrew Knox was
perhaps the well liked person I've worked with and with good reason. A funny, intelligent, hardworking Scot, he held our lab together during some bumpy times. I'll say more about Karen
later, but she deserves credit here for her wonderful contributions to the foundation of our
chemistry as well as helping me sort out the 1,6-enynes. To Jim Trenkle, Victor Gehling,
Katrina Woodin, Aaron Van Dyke, Graham Simpson and Neil 'I actually care about hockey'
Langille thanks for making the lab a better place to work in. A smart and hard working
undergraduate Brian Sparling has taken up a project that I had great interest in but could not do
myself. Thanks, and I'm sure he'll make it work. Thanks to Susan Brighton for her kind words
and sympathetic ear. Thanks to Professors Greg Fu, Steve Buchwald and Rick Danheiser who
have given me sound advice over the years. Professor Tim Swager has very generously accepted
me into his laboratory to do post-doctorial research. I'm thrilled to have the opportunity to learn
and work with him and his students. To my advisor Professor Timothy Jamison, your patience
with me has been astounding and I am a better chemist today than the day I walked into your
office. Because of you I'm better equipped to start my career and I will look back upon my time
in your lab fondly.
There is no way to possibly thank my best man Marlon for everything he's done for me, so I
will simply say that you are without any doubt the finest person that I have ever met or will ever
meet and I hope that you and Maddy have the happiest of lives together. I'd wish that you one
day got everything that you deserve, but then there would be nothing left for the rest of us! To
my friends Anna, Dave, Don, Shu and Zenon it has been a blessing knowing you.
Finally to my family. To my grandparents, who have loved myself and my siblings like we
were their own, thank you for raising such amazing children and installing in them the values
that they have passed on to me. I have two amazing and talented siblings, who are gifts to those
around them. My sister, Mairen blows me away; she's smart, creative, patient and an astounding
teacher. My brother, Ian is a wonderful know-it-all who one day will certainly be richer than any
man should be. Ian you're a good kid, do what you love and do it well and I'll always be proud
of you (then buy me a professional hockey team, but not the Leafs). Dad, for the rest of my life I
will never respect someone as much as I do you. I once said to you as you were rebuilding the
deck (it was a weekend and undoubtedly you'd already been at work for several hours) "If I was
twice the man that I am right now, then I'd be half the man that you are". You laughed and said
that was about right, but I was still young. I'd never been so honoured. I was grateful to think it
was true then, and no less grateful to think it is true now. I have also been blessed in my life
with the most loving mother imaginable. It seems that at every low point of my life I have been
able to count on my mother being there with unwavering love and support. Mom, I can't hope to
list all the things that you've done for me, but I do remember them. My greatest resources as an
organic chemist are still the notebooks you assembled from my first year notes at MIT after
Christmas! To my beautiful bride Karen, everything about you is a blessing. You've changed
my world, and made me a better person. I can't imagine being the person that I was before I fell
in love with you. These have been the greatest years of my life, and I hope that the rest of my
life can be spent trying to see your beautiful smile.
TABLE OF CONTENTS
Abbreviations
Chapter 1. Nickel-Catalyzed Reductive Coupling Reactions of Aldehydes
and Chiral 1,6-Enynes
Introduction
Origin of Regioselectivity in Nickel-Catalyzed Reductive Coupling
Reactions of Aldehydes and 1,6-Enynes
Diastereoselectivity in the Nickel-Catalyzed Reductive Coupling
Reactions of Chiral 1,6-Enynes
Carbocyclization
Conclusion
Experimental Section
IH NMR and 13 C NMR Spectra
Chapter 2. Total Synthesis of (+)-Acutiphycin
Introduction
Results and Discussion
Studies of Nickel-Catalyzed Reductive Fragment Coupling Operations
Consequences of the 1,6-Enyne Approach to (+)-Acutiphycin
Total Synthesis of (+)-Acutiphycin
Unanticipated Macrodiolide Formation
Macrolactonization Based Strategies
Conclusion
Experimental Section
IHNMR and 13C NMR Spectra
Curriculum Vitae
60
62
65
69
72
75
76
84
85
123
199
ABBREVIATIONS
Ac
Ar
BOM
Bn
Bu
"C
cod
CSA
Cy
Cyp
6
DCM
DMAP
DME
DMF
DMPU
DMSO
dr
ee
Et
eq
Fc
g
GC
h
HKR
HOAc
HPLC
HRMS
HWE
Hz
acetyl
aryl
benzoxymethyl
benzyl
butyl
degree (Celsius)
cyclooctadiene
(±)- 10-camphorsulfonic acid
cyclohexyl
cyclopentyl
chemical shift in parts per million
dichloromethane
4-dimethylaminopyridine
1,2-dimethoxyethane
N,N'-dimethylformamide
1,3-dimethyl-3,4,5,6-tetrahydro- 1(1H)-pyrimidinone
dimethyl sulfoxide
diastereomeric ratio
enantiomeric excess
ethyl
equation
ferrocenyl
gram
gas chromatography
hours
hydrolytic kinetic resolution of terminal epoxides
acetic acid
high performance liquid chromatography
high resolution mass spectrometry
Horner-Wadsworth-Emmons olefination
hertz
i-
iso-
IR
L
LDA
m
infrared
liters
lithium diisopropylamide
milli
m-
meta-
IL
M
Me
MeCN
MHz
min
mol
micro
molar
methyl
acetonitrile
megahertz
minutes
mole
Ms
mesyl
n-
normal-
NBS
NMDPP
NMO
NMR
nOe
N-bromosuccinimide
neomenthyldiphenylphosphine
morpholine-N-oxide
nuclear magnetic resonance
nuclear Overhauser effect
o-
ortho-
[O]
Oct
oxidation
octyl
p-
para-
Pd/C
Ph
PPTS
py
salen
sat.
palladium on carbon graphite
phenyl
pyridinium-para-toluenesulfonate
pyridine
retention factor
N,N'-bis(salicylidene)ethylendiamine
saturated
ttR
tertretention time
TBAF
TBDPS
TBS
THF
Tf
TLC
TMS
TPAP
Ts
wt
tetrabutylammonium fluoride
tert-butyl diphenylsilyl
tert-butyl dimethylsilyl
tetrahydrofuran
trifluoromethanesulfonate
thin layer chromatography
trimethylsilyl
tetrapropylammonium perruthenate
para-toluenesulfonate
weight
RF
Chapter 1
Nickel-Catalyzed Reductive Coupling Reactions of Aldehydes and Chiral
1,6-Enynes
Introduction
Substrate-directable reactions are an important class of selective organic transformations, and
understanding their mechanism of direction is paramount to their utility.' Directing groups have
been used to control reactivity and selectivity in a number of transition metal-catalyzed
transformations, including hydrostannation of alkynes, 2 Heck reactions,3 Pd- 4 and Ni-catalyzed5
allylations, and C-H and C-C bond activation.6
The nickel-catalyzed coupling of alkynes and aldehydes has emerged as a powerful method for
the efficient and selective preparation of allylic alcohols. 78' In most cases, the regioselectivity of
these coupling reactions is determined by a steric or electronic difference in the two alkyne
substituents. For example, previous investigations in our laboratory have shown that alkynes
conjugated to either an aryl or alkenyl substituent undergo nickel-catalyzed reductive coupling
with aldehydes with high regioselectivity (eq 1 ,2 ).8bdf
Ni(cod) 2 (cat.)
Ar --
R + R1CHO
PR 3 (cat.)
Et3 B
OH
Ar
R
(1)
R
>95 : 5 regioselectivity
R
R2
5
3
R
R4
+ R'CHO
R3
Ni(cod) 2 (cat.)
PR3 (cat.)
Et3 cat.)
B
3
R
OH
R R1
R2
R
5
(2)
(2)
R
>90 : 10 regioselectivity
Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307-1370.
(a) Rice, M. B.; Whitehead, S. L.; Horvath, C. M.; Muchnij, J. A.; Maleczka, R. E. Synthesis 2001,
1495-1504.
(b) Marshall, J. A.; Bourbeau, M. P. Tetrahedron Lett. 2003, 44, 1087-1089.
3 Review: Oestreich, M. Eur. J Org. Chem. 2005, 783-792.
4(a)
Krafft, M. E.; Fu, Z.; Procter, M. J.; Wilson, A. M. Pure & Apple. Chem. 1998, 70, 1083-1090. (b) Krafft, M.
E.; Wilson, A. M.; Fu, Z.; Procter, M. J.; Dasse, O. A. J. Org. Chem. 1998, 63, 1748-1749. (c) Krafft, M. E.;
Sugiura, M.; Abboud, K. A. J Am. Chem. Soc. 2001, 123, 9174-9175. (d) Nomura, N.; Tsurugi, K.; RajanBabu,
2
T. V.; Kondo, T. J Am. Chem. Soc. 2004, 126, 5354-5355.
Didiuk, M. T.; Morken, J. P.; Hoveyda, A. H. Tetrahedron 1998, 54, 1117-1130.
Review: Jun, C.-H.; Moon, C. W.; Lee, D.-Y. Chem. Eur. J 2002, 8, 2422-2428.
Montgomery, J. Angew. Chem. Int. Ed 2004, 43, 3890-3908.
8 (a) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065-9066. (b) Huang, W.-S., Chan, J.; Jamison,
T. F. Org. Lett. 2000, 2, 4221-4223. (c) Colby, E. A.; Jamison, T. F. J Org. Chem. 2003, 68, 156-166. (d) Miller,
K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442-3443. (e) Mahandru, G. M.; Liu, G.;
Montgomery, J. J Am. Chem. Soc. 2004, 126, 3698-3699. (f) Miller, K. M.; Luanphaisamnont, T.; Molinaro, C.;
Jamison, T. F. J Am. Chem. Soc. 2004, 126, 4130-4131.
Recently, our group reported a substrate-directed, nickel-catalyzed reductive coupling reaction
of 1,6-enynes and aldehydes in which regioselectivity was controlled by a tethered olefin. 9 In
the absence of a phosphine additive, the reaction proceeded with excellent regioselectivity for
1,6-enynes, while other enynes failed to react (Table 1). As enyne 4 is not significantly different
in a steric or electronic sense from alkynes 2, 3, or 5, it seems that involvement of the olefin in
the reaction occurs uniquely in the case of the 1,6-enyne. Additionally, since the conjugated 1,3enyne 1 failed to react, it appears that the origin of the high regioselectivity observed with 1,3enynes8f is fundamentally different than that observed with 1,6-enynes.
Table 1. Directing Effects of Tethered Alkenes"
Me
i-PrCHO
Ni(cod) 2
+ _,n-hex (10 mol%),
Et3B
EtOAc
1-5
OH
HO
Me
Me
n
n-hex Me
A
n
(3)
n-hex
B
n yield (%) regioselectivity (A: B) b
alkyne
entry
1
1
0
<5
-2
2
1
<5
-3
2
<5
-3
4
4
3
53c
>95:5
5
5
4
<5
-50 :50
28 c
6 n-pentyl-C-C-n-hexyl n.a.
" Standard procedure: The alkyne (0.50 mmol) was added to a 0 'C solution of Ni(cod) 2
(0.05 mmol), i-PrCHO (1.00 mmol), and Et 3B (1.00 mmol) in EtOAc (0.5 mL), and the
solution was allowed to stir 15 h at room temperature. b Determined by 1H NMR and/or GC. '
Some alkylative coupling (transfer of Et from Et 3B) also observed.
The effect of different phosphine additives on the regioselectivity of the reductive coupling
reaction of enyne 4 and isobutyraldehyde was also investigated (Table 2).10
Electron rich
phosphines afforded superior yields and, remarkably, with very large phosphines (cone angle
>1630), the sense of regioselectivity was completely reversed, giving >95:5 of regioisomer B
9 Miller, K. M.; Jamison, T. F. J.Am. Chem. Soc.2004, 126, 15342-15343.
'0Karen M. Miller, Selective, Nickel-Catalyzed Carbon-CarbonBond-Forming Reactions ofAlkynes, Ph.D. Thesis,
Massachusetts Institute of Technology, Cambridge, Massachusetts, June 2005.
(entries 1-3, Table 2).1
The use of even marginally smaller phosphines, resulted in a significant
loss of regioselectivity (entries 4-6, Table 2). Since no regioselectivity was observed when 6tridecyne was coupled to isobutyraldehyde in the presence of tricyclopentylphosphine (PCyp 3)
(77%, 50:50 regioselectivity) it is likely that the tethered olefin is responsible for the
regioselectivity both in the presence and absence of a phosphine additive.
Table 2. Effect of phosphine ligand on regioselectivity in reductive coupling reactions."
entry
PR 3
PR 3 cone angleb
A
B
condition
type
yieldc
1
PCyp 3
2
3
PCy 3
P(i-Pr) 3
NDd
1700
1610
5
5
5
>95
>95
>95
4
5
6
PFcPh 2
PCyPh 2
155oe
1520
1320
--
60
58
58
III
PBu 3
none
40
42
42
20
30
75
>95
5
1
50
7
50
II
30
25
" Conditions (see eq 3): 0.5 mmol scale, 10 mol% Ni(cod) 2, 20 mol% ligand, 100 mol% 4, 200 mol% i-PrCHO,
200 mol% Et 3B, EtOAc, 0 'C to RT, 15h. Regioselectivity determined by GC analysis. b Reference 11. C 10-15%
reductive cyclization product observed in all cases (see Scheme 7); yields are approximated based on 'H NMR
integration of the mixture. d A suitable literature value for the cone angle of PCyp 3 could not be found. e Reference
12.
Origin of Regioselectivity
in Nickel-Catalyzed
Reductive Coupling Reactions
of
Aldehydes and 1,6-Enynes
Although directing effects of tethered alkenes have been demonstrated in other metal-mediated
reactions, 13 the only other examples in which the sense of the effect was reversed by a catalytic
additive are the Pd-catalyzed enyne isomerizations reported by Trost. 14 In this case, high
regioselectivity was observed in only one direction (>15:1 vs. 1:2.5).
This reversal was
attributed to displacement of the olefin tether and a subsequent non-directed reaction, the
12
Phosphine properties taken from: Tamaru, Y. In Modern Organonickel Chemistry; Tamaru, Y., Ed.; WILEYVCH Verlag GmbH & Co. KgaA, Weinheim, 2005, pages 1-37 and references therein.
Otto, S.; Roodt, A.; Smith, J. Inorganica Chimica Acta, 2000, 303,
295-299.
Ni-catalyzed sp3-sp3 cross coupling: (a) Devasagayaraj, A.; Stiidemann, T.; Knochel, P. Angew. Chem. Int. Ed.
1995, 34, 2723-2725. (b) Krafft, M. E.; Sugiura, M.; Abboud, K. A. J Am. Chem. Soc. 2001, 123, 9174-9175. (c)
Nomura, N.; Tsurugi, K.; RaganBabu, T. V.; Kondo, T. J Am. Chem. Soc. 2004, 124, 5354-5355
14 Trost, B. M.; Tanoury, G. J.; Lautens, M.; Chan, C.; MacPherson, D. T. J Am. Chem. Soc. 1994, 116, 4255-4267.
'
regioselectivity of which was similar to that observed in the case of saturated analogues.
Conversely, in our system the addition of a variety of phosphine ligands results in a complete
reversal of regioselectivity, while others give mixtures of regioisomers. Therefore, the role of
the additive is dependant upon the structure of the phosphine, and in those conditions which are
highly regioselective the olefin likely directs regioselectivity.
The investigation of additive effects described in Table 2 suggests that three different
pathways are operative in these reactions depending upon the ligand employed.
These
conditions are defined by their regiochemical outcomes (Scheme 1): type I conditions are those
that exclusively form regioisomer A, type 11 conditions are those that exclusively form B, and
any condition that results in a mixture of regioisomers is type III. By assuming that coordination
on the nickel is three coordinate and planar,15 and that the metal center undergoes stereospecific
ligand substitution,16 a mechanistic rationale for each set of conditions can be proposed (Scheme
2).
17
Scheme 1
i-PrCHO
+
Ni(cod) 2
(10 mol%),
n-hex conditions-,
Et 3B
EtOAc
Me
HO
OH
Me
Me
3
n-hex Me
A
n-hex
B
type I: A only
type ll1: B only
type II1: a mixture of regioisomers
15P6rshke reported x-ray crystal structures of 3-coordinate Ni-diene and Ni-diyne complexes: (diene) Proft, B.;
P6rschke, K.-R.; Lutz, F.; Kriiger, C. Chem. Ber. 1991, 124, 2667-2675. (diyne) Proft, B.; P6rschke, K.-R.; Lutz,
F.; Krtiger, C. Chem. Ber. 1994, 127, 653-655.
16 In d8, square-planar complexes ligand substitution generally occurs through with retention of stereochemistry.
Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G. Principlesand Applications of OrganotransitionMetal
Chemistry; University Science Books: Mill Valley, California, 1987, pp 241-244.
17 Drawn as a Ni(II) complex for illustrative purposes, I do not know the oxidation state of the nickel prior to
formation of the C-C bond.
Scheme 2
pathway
B
RCHO
B
A
--
Me
Me
L
6
N
7
R
B
C-C bond
A
formation
Ni
Me
_
O
0
H
regioisomer A
R
pathway II
6
RCHO
B
PCyp 3
A
0
Nj
-
Me"
8
PCyp 3
IN
--
3
C-C bond
formation
regioisomer B
pathway III
RCHO
RCHO
-PBu
i-.
11
3
0
R
regioisomer A
12
+
regioisomer B
In all cases, C-C bond formation is believed to occur through an oxanickellacyclopentene.7 ' 8
The third ligand (L) is assumed to be an olefin18 and, as it is not part of a bidentate chelate, is
considered to be the most weakly bound ligand. Therefore, in substitution reactions of 6, L is the
ligand that is preferentially displaced from the metal center.
'8Ethylene, 1,5-cyclooctadiene, or another equivalent of the enyne are all possible.
In the absence of a phosphine ligand (Scheme 2, pathway I), ligand substitution places the
aldehyde 'cis' to the alkyne carbon distal to the alkene (C(A)) and 'cis' to the bound olefin,
giving 7. C-C bond formation occurs at C(A) while the olefin tether is coordinated to the nickel,
resulting in exclusive formation of regioisomer A. Displacement of L by a large phosphine (e.g.,
PCyp 3) gives complex 8 (Scheme 2, pathway II). As the phosphine, which is a better C-donar,
coordinates more strongly to the metal center than the tethered alkene, the latter is preferentially
displaced by the aldehyde in a stereospecific fashion, ultimately leading to regioisomer B by way
of 9. Thus, despite not being bound during the C-C bond formation, the olefin nevertheless
determines regioselectivity.
When a smaller phosphine (e.g., PBu 3) is employed, two
equivalents of phosphine are bound to the metal center, displacing both the olefin tether and L to
give 10. In this case, regioselectivity is not determined by the olefin, and a non-selective
displacement of either phosphine by the aldehyde leads to a mixture of 11 and 12, which in turn
affords a mixture of regioisomers A and B (Scheme 2, pathway III).
In order to test these mechanistic hypotheses and the overriding assumption of a planar, threecoordinate nickel complex, the effect of a stereogenic center in the olefin tether was evaluated. I
hypothesized that in the absence of a phosphine (type I), coordination of the olefin to the metal
center should enhance diastereoselection, while conditions employing achiral phosphines (types
II and III) should lead to lower diastereoselectivity since the olefin would be dissociated during
the C-C bond-forming step. Thus, chiral 1,6-enynes 13 and 14 were synthesized and coupled
with isobutyraldehyde under three distinct sets of catalytic conditions: (I) Ni(cod)2 with no
additive; (II) Ni(cod)2 + PCyp 3; and (III) Ni(cod) 2 + PBu 3 (Table 3).
Table 3. Coupling reactions of chiral 1,6-enynes
Me
+ i-PrCHO
ON"/ "
Me
R
R
15A. 16A
13: R = Et
14: R = t-Bu
entry
1
Me
0
conditions
enyne
entry enyne
13
reaction
reaction
conditions
products
I
OH
R
OH
MO
Me
SMe
+
Me
Me
1B51
15: R = Et
16: R = t-Bu
16B
A :B b
dr A c
dr B c
>95:5
95:5
--
<5:95
--
45:55
2
II
3
III
55:45
50:50
45:55
1
>95:5
>95 : 5
--
<5:95
--
42:58
51:49
45:55
42:58
4
14
5
6
II
15A, B
16A, B
(RIII
" I: Ni(cod) 2 (10 mol%), Et3B (200 mol%). II: Reaction conditions I + PCyp 3 (20 mol%). III: Reaction conditions I
+ PBu 3 (20 mol%). b Based on isolated yields.' Determined by 'H NMR.
As predicted, under type I reaction conditions (no phosphine) both enynes gave exclusively
regioisomer A (Table 3, entries 1 and 4). In addition, both allylic alcohols were formed in
excellent diastereoselectivity, indicating a strong influence of the stereogenic center in the tether,
despite being removed from the site of C-C bond formation by 5 atoms (1,6-induction).
Conversely, under type II reaction conditions regioisomer B is formed exclusively, but
diastereoselection is negligible (entries 2 and 5).
Type III reaction conditions are neither
regioselective nor diastereoselective (entries 3 and 6).
Taken together, these experiments strongly support the notion that, in the absence of phosphine
(type I), the alkene is coordinated to nickel during the C-C bond-forming step and that, in the
presence of phosphine (type II or III), the alkene is not coordinated to nickel during the C-C
bond-forming step.
In other words, the critical aspect of the type II and III mechanistic pathways is that the
phosphine is bound to nickel during the C-C bond forming step. I reasoned that since the
influence of the chiral center in the tether in these cases is minimal, any diastereoselectivity
induced by a chiral phosphine could be attributed to the phosphine alone, a result that would be
consistent with phosphine being bound to nickel as the C-C bond is formed.
To this end, I subjected enyne 13 and isobutyraldehyde to reductive coupling conditions in the
presence of both achiral and chiral ferrocenyl-containing phosphines (Table 4 ).8 c,19,20 Nearly
equimolar amounts of regioisomers A and B were obtained in all cases, suggesting that the
reaction occurs via a type III mechanistic pathway (cf. Scheme 2). Both the R and S phosphine
ligands afforded modest diastereoinduction for the formation of each regioisomer and,
importantly, the enantiomers of the chiral phosphine ligands favored the formation of the
opposite allylic alcohol stereocenter.
These results demonstrate that the enyne stereocenter
exerts little to no influence on the diastereoselectivity under these conditions and that the
phosphine is clearly bound to nickel during the C-C bond-forming step.
use of these phosphines in other nickel-catalyzed reductive couplings see: Miller, K. M.; Jamison, T. F. Org.
Lett. 2005, 7, 3077-3080.
20 Ferrocenyl-phosphines were chosen because they exhibit the highest level of enantioinduction with dialkylsubstituted alkynes, to which 9, 11, and 12 are analogous. See ref 8c.
19For
Table 4. Coupling reactions of chiral, enantiomerically enriched 13" with ferrocenyl-containing
phosphines
i-PrCHO
+
Ni(cod) 2 (10 mol%),
ligand (20 mol%)
Me
eO
15A + 15B
Et3B
i-Pr
Et
>90% ee
% "/' Fc (R)-17
13
Ph
dr 15A (R:S) c
dr 15B d
48 : 52
30 : 70
28 : 72
(S)-17
55 : 45
66: 34
68 : 32
FcPPh 2
54: 46
56 : 44
48 : 52
ligand
A:B
(R)-17
b
See Scheme 3. b Based on isolated yields.
Relative stereochemistry not determined.
Configuration of allylic alcohol stereogenic center.
d
Diastereoselectivity in the Nickel-Catalyzed Coupling Reactions of Chiral 1,6-Enynes
The high levels of diastereoselectivity afforded by enynes 13 and 14 in the absence of
phosphine (Table 1, entries 1 and 4), prompted us to investigate coupling reactions of these
chiral enynes further.
In order to determine the sense of induction in the formation of
regioisomer A, enantiomerically enriched enyne 13 was prepared (Scheme 3). 1-Penten-3-ol was
resolved using a Sharpless kinetic resolution, 21' 22 and Williamson ether synthesis using the (+)-1penten-3-ol afforded enyne (S)-13.
21 For
the synthesis of (+)-l-penten-3-ol using Sharpless kinetic resolution see: Hill, M. L.; Raphael, R. A.
Tetrahedron, 1990, 46, 4487-4594.
22 For optical rotation of (+)-l-penten-3-ol Kagan, H. B, Stereochemistry, George Thieme, Stuttgart, 1977, vol. 4,
page 224.
Scheme 3
OH
Me
OH
NaH, THF
D-(-)-DIPT,
Me
t-BuOOH,
Me
CH2CI2
[OX]D = +21.3 Br
0
MO
Et
(S)-13
[a]D = -75.7
>90% ee
Scheme 4
(S)-13
+
i-PrCHO
Ni(cod) 2
10 m%)
Et3 B .
OH
Me
O
Et
Me
1. Ac20, NEt 3,
DMAP
Me 2. 03, PPh 3
Me
15A
O
Me
Me
Me
OAc
(+)-18
[a]D = +6.7
Nickel-catalyzed reductive coupling of (S)-13 and isobutyraldehyde in the absence of a
phosphine (type I reaction conditions) afforded 15A in >95:5 regioselectivity and 95:5
diastereoselectivity (Scheme 4). Conversion to the corresponding acetate followed by ozonolysis
afforded ketone (+)-18. The sign of the specific rotation of this compound was opposite that of
(-)-18 prepared from commercially available (S)-2-hydroxy-3-methylbutyric
acid,2 3 thus
establishing the allylic alcohol configuration in 15A as R.
One possible explanation for the high diastereoselectivity was that the oxygen in the ethereal
tether was binding to the aldehyde via the boron (Figure 1), thus directing the aldehyde to the top
face due to the conformation of the ring chelate.
Figure 1
Xn
,B.
MeN
23
L
Bach, J.; Berenguer, R.; Farris, J.; Garcia, J.; Meseguer, J.; Vilarrasa, J. Tetrahedron:Asymmetry, 1995, 6, 26832686.
To evaluate whether the oxygen atom in the tether plays a significant role in the reaction, a
1,6-enyne (19) in which the oxygen was replaced with a methylene group was synthesized by
way of a highly diastereoselective Myers alkylation, followed by Swern oxidation and Wittig
olefination (Scheme 5)24 . Enyne 19 would be unable to direct the reaction via a dative bond with
the boron-species (Figure 1). Therefore, it was predicted that the regioselectivity of the coupling
of 19 with isobutyraldehyde under type I conditions would be significantly diminished as
compared to 13 (Table 3, entry 1).
Scheme 5
1. LDA, LiCI, THF
e Ph
MN
0
Et
Me
OH
20
Me
2.
OH
Et
-Me
3. LDA, H3B*NH 3 , THF
21, >90% ee
(COCd) 2 ,
DMSO
Me
Et
19, [a]D = -21.1
BrCH 3 PPh 3 , KOt-Bu
Et-
NEt 3,
THF
H
Et2 0
22
However, under type I coupling conditions enyne 19 gave results similar to those obtained
with the enynes possessing an ethereal tether. Nickel-catalyzed reductive coupling of 19 and
isobutyraldehyde afforded allylic alcohol 23 in very high regioselectivity and in slightly reduced
but nevertheless high, diastereoselectivity (Scheme 6). The sense of induction, determined to be
R using the same sequence of operations shown in Scheme 4, was also the same as that observed
24Myers,
A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119,
6496-6511.
with 13. Thus, an oxygen atom and a methylene group at this position in the tether have similar
(albeit measurably different) effects in type I coupling reactions.
Scheme 6
Me
i-rCHO MMe
Ni(cod) 2
Et3 B
Et
19
Me
M
Et
Me
Me
23
91:9 dr
Me
O
1. Ac20, NEt 3 ,
DMAP
DMAP Me
Me
2. 03, PPh 3
OAc
(+)-18, [a]D = +7.7
The exact mode of diastereoinduction is unknown. The size of the alkyl substituent of the
chiral center has very little effect on the diastereoinduction (Table 3, entries 1 and 4), and the
oxygen of the ethereal tether does not appear to be involved in chelation. Therefore, it is likely
that the alkyl substituent controls the conformation of the ring chelate, and it is the conformation
of the ring chelate rather than the chiral center itself that interacts with the aldehyde and
determines the stereochemical outcome of the reaction.
Carbocyclization
In the presence of a phosphine additive, carbocycle 24 is observed as a minor product of
nickel-catalyzed coupling reactions of 1,6-enynes and aldehydes (Scheme 7).9 This compound is
thought to arise from complex 8 in a manner analogous to the nickel(0)-promoted enyne
cyclizations previously reported by Tamao et al.25 I propose that this background reaction is
seen most frequently in the presence of a phosphine additive because the formation of 9 (from 8)
should be slow relative to the formation of 7 (from 6), since L is presumed to be more weakly
25 Tamao, K.; Kobayashi, K.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 1286-1288.
bound than the tethered olefin. The additional time that the enyne spends complexed to the
metal center in the absence of the aldehyde favors carbocyclization of 8.
Scheme 7
X
M e9
NP
iPR
NX
3
i-PrCHO
PR3
R
Et3B
R'
24
R'
8
Me
X-X
Me
Me
k i i-PrCHO
X
i-Pr
RNiH
O
R
PR 3
9
X
X
,-PrCHO
X~
N
R'
L
k2
k2 >k
k2 >k 1
R'
6
O
7
i-Pr
Conclusion
Three distinct mechanistic pathways and their associated reaction conditions have been
described, and our observations support the hypothesis that nickel-catalyzed reductive coupling
reactions of alkynes and aldehydes proceed through an approximately planar, three-coordinate
nickel-complex.
These results also strongly support the theory that ligand substitution is
occuring stereospecifically at the nickel center with retention of stereochemistry. 26
The
mechanistic insight gained through this investigation should facilitate the development of other
selective, nickel-catalyzed transformations.
2'The
mode of ligand substitution associative/dissociative is not known.
Experimental Section
Please see reference 10 for details regarding Tables 1 and 2.
General Methods
Unless otherwise noted, all reactions were performed under an oxygen-free atmosphere of
argon using standard Schlenk-line techniques. Bis(cyclooctadienyl)-nickel(0) (Ni(cod) 2), and
tricyclopentylphosphine (PCyp 3) were purchased from Strem Chemicals, Inc. and used without
further purification. Triethylborane (Et 3B), triethylamine, dimethylsulfoxide, tributylphosphine
(PBu 3), and penten-3-ol were purchased from Aldrich Chemical Co. and, unless otherwise stated,
used as received.
Isobutyraldehyde (Alfa Aeser) was distilled from anhydrous magnesium
sulfate (MgSO 4) prior to use. Diisopropylamine was distilled from calcium hydride and stored
over potassium hydroxide. (±)-4,4-Dimethyl-penten-3-ol was synthesized according to literature
procedure, and distilled prior to use.2 7 Tetrahydrofuran (THF) and diethyl ether were freshly
distilled over sodium/benzophenone ketyl, and dichloromethane (DCM) was freshly distilled
from calcium hydride.
1H
NMR was performed on a 500 MHz Varian instrument,
13C
NMR was performed on a 500
MHz Varian instrument equipped with an inverse probe, and in all cases the solvent was
deuterochloroform (CDCl 3) which had been filtered through activated basic alumina prior to use.
Infrared (IR) spectra were recorded as a thin film between NaCl plates on a Perkin-Elmer Model
2000 FT-IR System transform spectrometer.
High resolution mass spectra (HRMS) were
obtained on a Bruker Daltonics APEXII 3 Tesla Fourier Transform Mass Spectrometer by the
Massachusetts Institute of Technology Department of Chemistry Facility.
(+)-Penten-3-ol:
OH
27
Midland, M. M.; Koops, R. W. J Org. Chem. 1990, 55, 5058-5065.
Synthesized according to the literature. 21 Flame-dried molecular sieves 4 A (c. 5 g) were
loaded into a 100 mL round bottomed flask filled with CH 2CI 2 (25 mL). To this suspension was
added diisopropyl D-tartrate (D-(-)-DIPT) (350 ld,2.1 mmol) and racemic penten-3-ol (3.0 g,
34 mmol). The suspension was cooled to -5 oC and Ti(Oi-Pr) 4 (41 pl, 1.4 mmol) was added.
The reaction was stirred for 30 minutes, and then t-BuOOH (5.5 M in decanes, 6.0 mL, 33
mmol) was added. The reaction was warmed to 0 oC and stirred for 7 hours. The slurry was
added to a solution of iron(II) sulfate (11 g) and citric acid (3.5 g) in water (30 mL) and diluted
with ether (80 mL). The layers were separated and the aqueous layer extracted once with diethyl
ether.
The combined organics were washed with brine, dried over magnesium sulfate and
filtered. Solvent was removed under atmospheric pressure via distillation through a Vigereux
column (10 cm). Fractional distillation (20 torr, 50
oC)
of the residue then provided (+)-penten-
3-ol as a clear oil (1.0 g, 33% yield). [a]D +21.6 (c 0.37, 22 'C, CHCI 3). The optical rotation
was compared to literature values,22 and the stereocenter was determined to be (S).
(-)-3-But-2-ynyloxypent-1-ene (13):
Me
Et
13
Sodium hydride (7.5 g, -58%, -180 mmol) was loaded into a round bottom flask and rinsed
with anhydrous pentanes (3 x 50 mL) and dried in vacuo. THF (200 mL) was added followed by
addition of (+)-penten-3-ol (3.1 mL, 30 mmol), and the mixture was stirred for 3 hours at room
temperature prior to addition of 1-bromo-2-butyne (5.25 mL, 60 mmol). After stirring overnight,
the reaction was quenched by careful addition of saturated aqueous ammonium chloride. The
organics were extracted with diethyl ether (3 x 150 mL), washed with brine, dried over
magnesium sulfate, filtered and concentrated (0 'C, 50 torr). The product (as a solution in THF)
was loaded directly onto silica (7 cm x 5 cm) and purified by silica gel chromatography (10:1
pentanes:diethyl ether). Removal of the solvent (0 'C, 50 torr) followed by distillation through a
short path apparatus (35 oC, 1 torr) yielded (-)-13 as a clear oil (3.8 g, 92%, >90% ee).
[a]D -75.7 (c 3.09, CHC13, 22
(-)-13:
chiral GC analysis (Varian CP-3800, G-TA column, 50 "C,
0.7 mL/min H2 carrier) TR (S) 14.4 min, TR (R) 14.9 min; IR 2964 (m), 2924 (s), 2856 (m), 2248
oC);
(w), 1457 (b, w), 1057 (s), 910 (s) cm-; 'H NMR (500 MHz, CDCI 3)6 5.63 (ddd, J= 17.0, 11.0,
8.5 Hz, 1H), 5.23 (dd, J= 8.5, 2.0 Hz, 1H), 5.22 (dd, J= 17.0, 2.0 Hz, 1H), 4.15 (dq, Jd = 15.0
Hz, Jq= 2 .0Hz, 1H), 3.97 (dq, Jd= 15.0 Hz,Jq = 2.0 Hz, 1H), 3.73 (q, J= 7.0 Hz, 1H), 1.86 (t, J
= 2.0 Hz, 3H), 1.66 (apparent septet, J= 7.0 Hz, 1H), 1.52 (apparent septet, J= 7.0 Hz, 1H), 0.91
(t, J =7.5 Hz, 3H). 13C NMR (125.8 MHz, CDC13) 3 138.3, 118.1, 81.9, 81.8, 75.8, 56.1, 28.3,
9.9, 3.9.
(±)-3-But-2-ynyloxy-4,4-dimethylpent-l-ene
(14):
Me
t-Bu
14
According to the procedure for 13, (±)-4,4-dimethyl-penten-3-ol (1.71 g, 15.0 mmol) was
reacted with 600 mol% NaH and 300 mol% 1-bromo-2-butyne to give 2 g (80%) of a clear oil
after chromatography (25:1 pentanes:diethyl ether) and distillation (65 'C, 1 torr). 14: IR 2956
(s), 2870 (m), 2361 (w), 1464 (b, w), 1363 (m), 1136 (m)cm'; 'H NMR (500 MHz, CDCl 3) 3
5.68 (ddd, J= 17.0, 10.5, 8.5 Hz, 1H), 5.27 (dd, J= 10.5, 1.5 Hz, 1H), 5.19 (dd, J= 17.0, 1.5 Hz,
1H), 4.14 (dq, Jd= 15.0 Hz, Jq = 2.0 Hz, 1H), 3.92 (dq, Jd = 15.0 Hz, Jq = 2.0 Hz, 1H), 3.42 (d, J
= 8.5 Hz, 1H), 1.86 (t, J = 2.0 Hz, 3H), 0.91 (s, 9H). 13C NMR (125.8 MHz, CDC13) 6 135.4,
119.2, 88.0, 81.5, 76.1, 56.4, 34.4, 26.3, 3.9; HRMS m/z (ESI, M + Na+) calcd 189.1250 found
189.1256.
General procedure for nickel-catalyzed reductive coupling:
In a glovebox, Ni(cod) 2 (14 mg,0.050 mmol, 10 mol%) was added to a pre-dried 10 mL round
bottom flask, if phosphine was included it was added (20 mol%) at this time. The flask was then
placed under Argon on a Schlenk-line and neat Et 3B was added (0.15 mL, 1.0 mmol,200 mol%).
The solution was cooled to 0 oC and the i-PrCHO (90 pLi,
1.0 mmol, 200 mol%) was added
dropwise. The reaction was stirred for 3 minutes and then the 1,6-enyne (0.5 mmol) was added
in a single portion. The ice bath was allowed to warm to room temperature overnight. After 15
hours and the reactions were diluted with reagent grade EtOAc and then opened to the
atmosphere and stirred for 30 minutes. Solvent was removed in vacuo and crude material was
purified via silica gel chromatography.
OJ
Et
Me
MMe
OH
Me
M+ i-PrCHO--
0
Me +
Et
13
Me
Me
15A
O DMe
Et
OH
15B
13 + i-PrCHO.
no phosphine: 13 (69 mg, 0.50 mmol) was reacted with i-PrCHO (90 gL, 1.0 mmol) in the
presence of Ni(cod) 2 (14 mg, 0.050 mmol) and Et 3B (0.15 mL, 1.0 mmol). Crude material was
purified by silica gel chromatography with 15:1 hexanes:diethyl ether 4 7:1 hexanes:ethyl
acetate to give 59 mg (56%) of 15A as a clear oil. RF = 0.30 (6:1 hexanes:EtOAc, KMnO 4)
(single regioisomer, 95:5 mixture of S,R and S,S).
PCyp 3 : 13 (69 mg, 0.50 mmol) was reacted with i-PrCHO (90 [1 L, 1.0 mmol) in the presence
of Ni(cod) 2 (14 mg, 0.050 mmol), PCyp 3 (28 pL, 0.10 mmol), and Et 3B (0.15 mL, 1.0 mmol).
Crude material was purified by silica gel chromatography with 15:1 hexanes:diethyl ether - 9:1
hexanes:ethyl acetate to give 25 mg (24%) of 15B as a clear oil RF = 0.46 (6:1 hexanes:EtOAc,
KMnO 4 ) (single regioisomer, 55:45 mixture of diastereomers).
PBu 3 : 13 (69 mg, 0.50 mmol) was reacted with i-PrCHO (90 gL, 1.0 mmol) in the presence of
Ni(cod) 2 (14 mg, 0.050 mmol), PBu 3 (25 gL,0.10 mmol), and Et3B (0.15 mL, 1.0 mmol). Crude
material was purified by silica gel chromatography with 15:1 hexanes:diethyl ether -
9:1
hexanes:ethyl acetate to give 19.3 mg (18%) of 15A and 16 mg (15%) of 15B as clear oils (15A:
50:50 mixture of diastereomers; 15B: 55:45 mixture of diastereomers).
(R)-17:28 13 (69 mg, 0.50 mmol) was reacted with i-PrCHO (90 [L, 1.0 mmol) in the presence
of Ni(cod) 2 (14 mg, 0.050 mmol), (R)-17 (41 mg, 0.10 mmol), and Et 3B (0.15 mL, 1.0 mmol).
Crude material was purified by silica gel chromatography with 15:1 hexanes:diethyl ether - 9:1
28
Miller, K. M.; Colby, E.A.; Woodin, K. S.; Jamison, T. F. Adv. Synth. Catal.
2005, 347, 1533-1536.
hexanes:ethyl acetate to give 9 mg (8%) of 15A and 10 mg (9%) of 15B as clear oils (15A:
30:70 mixture of S,R : S,S; 15B: 72:28 mixture of diastereomers).
(S)-17: 28 13 (69 mg, 0.50 mmol) was reacted with i-PrCHO (90 ptL, 1.0 mmol) in the presence
of Ni(cod) 2 (14 mg, 0.050 mmol), (S)-17 (41 mg, 0.10 mmol), and Et 3B (0.15 mL, 1.0 mmol).
Crude material was purified by silica gel chromatography with 15:1 hexanes:diethyl ether - 9:1
hexanes:ethyl acetate to give 10.6 mg (10%) of 15A and 8.9 mg (9%) of 15B as clear oils (15A:
66:34 mixture of S,R : S, S; 15B: 32:68 mixture of diastereomers).
FcPPh 2 : 13 (69 mg, 0.50 mmol) was reacted with i-PrCHO (90 jtL, 1.0 mmol) in the presence
of Ni(cod) 2 (14 mg, 0.050 mmol), FcPPh 2 (37 mg, 0.10 mmol), and Et 3B (0.15 mL, 1.0 mmol).
Crude material was purified by silica gel chromatography with 15:1 hexanes:diethyl ether -) 9:1
hexanes:ethyl acetate to give 8.2 mg (7%) of 15A and 7.2 mg (6%)of 15B as clear oils (15A:
56:44 mixture of S,R : S,S; 15B: 52:48 mixture of diastereomers).
15A: [a]D -23.4 (c 0.86, CHC13, 22 'C); IR 3429 (b, m), 2962 (s), 2934 (s), 2872 (s), 1465 (m),
1094 (s), 1017 (s);1H NMR (500 MHz, CDC13) -data is for S, R diastereomer- 6 5.68 (ddd, J=
17.0, 10.5, 8.0 Hz, 1H), 5.55 (t, J = 6.0 Hz, 1H), 5.20 (dd, J = 10.5, 1.0 Hz, 1H), 5.18 (dd, J =
17.0, 1.0 Hz, 1H), 4.10 (dd, J
=
12.0, 6.5 Hz, 1H), 3.90 (dd, J= 12.0 Hz, 6.5 Hz, 1H), 3.64 (dd, J
= 8.0, 3.0 Hz, 1H), 3.56 (q, J= 6.5 Hz, 1H), 1.78 (apparent hex, J= 6.5 Hz, 1H), 1.62 (m, 1H),
1.60 (s, 3H), 1.55 (OH) (bs, 1H), 1.49 (apparent sept, J= 7.0, 1H), 0.98 (d, J=- 6.5, 3H), 0.90 (t,
J= 7.5 Hz, 3H), 0.81 (d, J= 6.5 Hz, 3H);
13C
NMR (125.8 MHz, CDCl 3) 5 140.3, 139.3, 124.5,
117.2, 83.6, 82.4, 64.5, 31.0, 28.5, 19.6, 18.5, 11.9, 10.0; HRMS m/z (ESI, M + Na+) calcd
235.1669 found 235.1670.
The S, S diastereomer was not directly synthesized; however, those peaks which were
resolvable from the S, R diastereomer were: 'H NMR (500 MHz, CDC13) 6 4.06 (dd, J = 12.0,
5.5 Hz, 1H), 3.94 (dd, J= 12.0, 7.0 Hz, 1H).
15B: IR 3454 (b, m), 2962 (s), 2934 (s), 2872 (s), 1669 (w), 1466 (m), 1319 (m), 1056 (s); the
diastereomers were not separated, peaks belonging to a specific diastereomer are indicated by
subscripts A or B, those peaks labeled A were favored with achiral phosphines and (R)-17. 'H
NMR (500 MHz, CDC13) 6 5.70 (m, IH), 5.64 (m, 1H), 5.24 (m, 2H), 4 .3 0A (d, J= 11.0, 1H),
4 .09B
(d, J = 11.0 Hz, 1H),
4
.048 (d, J = 11.0 Hz, 1H),
3 . 8 0A
(d, J = 11.0 Hz, IH), 3.58 (m, 2H),
2.86 (OH) (d, J= 7.0, IH), 1.80 (m, 1H), 1.69 (apparent t, J = 7.0, 3H), 1.63 (M, 1H), 1.52 (m,
IH), 1.03A (d, J= 6.0 Hz, 3H), 1.03B (d, J= 6.0 Hz, 3H), 0. 9 1 A (t, J= 7.5 Hz, 3H), 0. 8 9 B (t, J=
7.5 Hz, 3H), 0. 7 7 A (d, J = 6.0 Hz, 3H), 0. 7 5 B (d, J = 6.0 Hz, 3H); no attempt was made to
specify which carbon signals belonged to each diastereomer, there are exactly double the number
of expected signals for a single compound.
13
C NMR (125.8 MHz, CDC13) 6 138.7, 138.7,
127.2, 127.0, 118.0, 117.8, 84.3, 84.0, 83.6, 83.3, 64.5, 64.2, 32.6, 32.5, 28.6, 28.5, 19.8, 19.8,
19.3, 19.2, 13.4, 13.4, 10.1, 9.9; HRMS m/z (ESI, M + Na t ) calcd 235.1669 found 235.1672.
MOH OMe
-Or
Me+ i-PrCHO-
t-Bu
Me + '
Me
0
t-Bu
14
Me
Me
Me
OI
Me
t-Bu
16A
OH
16B
14 + i-PrCHO: relative stereochemistry of 16A based on analogy to 15A.
no phosphine: 14 (83 mg, 0.50 mmol) was reacted with i-PrCHO (90 [pL, 1.0 mmol) in the
presence of Ni(cod) 2 (14 mg, 0.050 mmol) and Et 3B (0.15 mL, 1.0 mmol). Crude material was
purified by silica gel chromatography with 15:1 hexanes:diethyl ether -
8:1 hexanes:ethyl
acetate to give 33 mg (28%) of 16A as a clear oil RF = 0.43 (6:1 hexanes:EtOAc, KMnO 4)
(single regioisomer, >95:5 (±) S, S: S, R).
PCyp 3 : 14 (83 mg, 0.50 mmol) was reacted with i-PrCHO (90 gLL, 1.0 mmol) in the presence
of Ni(cod) 2 (14 mg, 0.050 mmol), PCyp 3 (28 [pL, 0.10 mmol), and Et 3B (0.15 mL, 1.0 mmol).
Crude material was purified by silica gel chromatography with 15:1 hexanes:diethyl ether 4 9:1
hexanes:ethyl acetate to give 22 mg (18%) of 16B as a clear oil RF = 0.55 (6:1 hexanes:EtOAc,
KMnO 4) (single regioisomer, 42:58 mixture of diastereomers).
PBu 3 : 14 (83 mg, 0.5 mmol) was reacted with i-PrCHO (90 pgL, 1.0 mmol) in the presence of
Ni(cod) 2 (14 mg, 0.05 mmol), PBu 3 (25 tL, 0.1 mmol), and Et 3B (0.15 mL, 1.0 mmol). Crude
material was purified by silica gel chromatography with 15:1 hexanes:diethyl ether -
9:1
hexanes:ethyl acetate to give 15.6 mg (13%) of 16A and 14.8 mg (12%) of 16B as clear oils
(16A: 45:55 mixture of diastereomers; 16B: 42:58 mixture of diastereomers).
16A: IR 3411 (b, m), 2962 (s), 2956 (s), 2872 (s), 2870 (s), 2361 (w), 1465 (m), 1363 (s), 1016
(b, s), 925 (s); 'H NMR (500 MHz, CDC13) -data is for (+)-R, R diastereomer- 6 5.72 (ddd, J =
17.5, 10.0, 8.5 Hz, 1H), 5.52 (t, J= 6.0 Hz, 1H), 5.25 (dd, J= 10.0, 1.5 Hz, 1H), 5.14 (dd, J=
17.5, 1.5 Hz, 1H), 4.08 (dd, J= 12.5, 6.0 Hz, 1H), 3.86 (dd, J= 12.5 Hz, 7.0 Hz, 1H), 3.64 (dd, J
= 8.5, 3.0 Hz, 1H), 3.21 (d, J
=
8.5 Hz, 1H), 1.78 (apparent hex, J = 7.0 Hz, 1H), 1.60 (s, 3H),
1.54 (OH) (d, J = 3.0 Hz, 1H), 0.99 (d, J= 7.0, 3H), 0.88 (s, 9H), 0.82 (d, J = 7.0 Hz, 3H),
13
C
NMR (125.8 MHz, CDC13) 8 140.3, 139.3, 124.5, 117.2, 83.6, 82.4, 64.5, 31.0, 28.5, 19.6, 18.5,
11.9, 10.0; HRMS m/z (ESI, M + Na +) calcd 263.1982 found 263.1982.
The (±)-R, S diastereomer was not directly synthesized; however, those peaks which were
resolvable from the (±)-R, R diastereomer were: 'H NMR (500 MHz, CDC13) 6 4.05 (dd, J =
12.5, 5.5 Hz, 1H), 3.23 (d, J= 8.5 Hz, 1H), 0.97 (d, J=6.5 Hz, 3H), 0.89 (s, 9H).
16B: IR 3462 (b, m), 2956 (s), 2870 (s), 2361 (w), 1670 (b, w), 1465 (m), 1364 (m) 1068 (s);
the diastereomers were not separated, peaks belonging to a specific diastereomer are indicated by
subscripts A or B, with achiral phosphines A was the major product. 'H NMR (500 MHz,
CDC13) 6 5.72 (m, 1H), 5.61 (apparent q, J= 6.5, 1H), 5.3 2 A (dd, J= 10.5, 2.0 Hz, 1H), 5 .3 1 B
(dd, J= 10.5, 2.0 Hz, 1H), 5.21 (d, J= 17.5 Hz, 1H), 4.29B (d, J= 11.0, 1H), 4.08A (d, J = 11.0
Hz, 1H), 3 .9 4 A(d, J= 11.0 Hz, 1H), 3 .7 4 B(d, J= 11.0 Hz, 1H), 3.56 (q, J= 7.0, 1H), 3 .2 7 B(d, J
= 8.0 Hz, 1H), 3 .2 3 A(d, J= 8.0 Hz, 1 H), 2 .8 5 B(OH) (d, J= 7.0 Hz, 1H), 2 .82 A(OH) (d, J= 7.0
Hz, 1H), 1.80 (m, 1H), 1.66 (m, 3H), 1.63 (M, 1H), 1.03 (apparent t, J= 6.5 Hz, 3H), 0. 9 0B (S,
9H), 0. 89 A (S, 9H), 0.76 (apparent t, J = 6.0 Hz, 3H); no attempt was made to specify which
carbon signals belonged to each diastereomer, there are exactly double the number of expected
signals for a single compound.
13
C NMR (125.8 MHz, CDC13) 6 137.3, 137.1, 135.9, 135.8,
126.8, 126.7, 119.5, 119.3, 90.6, 90.6, 84.4, 84.3, 65.0, 64.8, 34.6, 34.6, 32.5, 32.4, 26.4, 26.3,
19.9, 19.8, 19.3, 19.3, 13.4, 13.4; HRMS m/z (ESI, M + Na+) calcd 263.1982 found 263.1986.
(+)-3-acetoxy-4-methylpentan-2-one (18):
O
Me
Me
Me
OAc
18
To a cold (0
solution of (-)-15A (35 mg, 0.16 mmol) in CH 2C12 (1.5 mL) was added NEt 3
oC)
(71 p.L, 0.51 mmol), Ac 20 (24 iiL, 0.25 mmol), and DMAP (2 mg, 0.02 mmol). The mixture
was warmed to room temperature and stirred for 1.5 hours. At this point it was concentrated in
vacuo and filtered through silica eluting with 10:1 hexanes:ethyl acetate. This afforded the crude
acetate-protected product which was carried on to the ozonolysis without purification.
The
intermediate was dissolved in CH 2C12 (3 mL) cooled to -78 'C and exposed to 03 until the
reaction was dark blue. The solution was then degassed with argon and PPh 3 (600 mg) was
added. The reaction was allowed to warm to 0 oC over 4 hours, and then concentrated in vacuo.
The crude material was loaded onto a column (15:1 pentanes:CH2Cl2) with a minimal amount of
CH 2C12 and then eluted with 15:1 pentanes:CH 2C12 until separation of PPh 3 and byproducts was
complete, then column was flushed with 1:1 pentanes:diethyl ether to give (+)-18 as a clear oil
(15 mg, 58 % over two steps). [a]D +6.7 (c 1.01, CH 2C1 2, 22 'C); 'H NMR (500 MHz, CDC13) 6
4.87 (d, J= 4.0 Hz, 1H), 2.24 (m, 1H), 2.17 (s, 3H), 2.16 (s, 3H), 1.01 (d, J= 7.0 Hz, 3H), 0.93
(d, J= 7.0 Hz, 3H);
13
C NMR (125.8 MHz, CDC13)6 205.6, 171.0, 83.0, 29.6, 27.2, 20.8, 19.4,
17.0.
(+)-18: Following the listed procedure 23 (42 mg, 0.20 mmol) was converted to (+)-18 (20 mg,
66%) over two steps. [a]D +7.7 (c 1.4, CH 2C12 , 22 'C).
(-)-2-But-2-ynyloxybutan-1-ol (21):
O
Me
C
+
Me
Me..J.Ph
N
Et •E
THF
iN
-
H
)H
0O
Me
.•.
N
Me
THF
1
OH
2Me
21
Me
OH
20
LDA,
H3BNH 3 ,Et
THF
Ph LDA, LiCI,
e
(4'
The synthesis of 21 was accomplished following the work of Myers and co-workers (eq 4).29
Butyryl chloride (3.1 mL, 30 mmol) was added dropwise to a chilled (0 'C) solution of (+)-(S,
S)-pseudoephedrine (4.95 g, 30.0 mmol) and NEt 3 (5.4 mL, 39 mmol) in THF (10 mL). The
reaction was stirred for 30 minutes and then quenched by the addition of water. The product
mixture was partitioned between ethyl acetate and brine, the organic layer was separated, washed
2 times with brine, and then dried over sodium sulfate. The solvent was removed in vacuo and
the crude solid recrystallized from toluene (20 mL) to give 20 as white crystals (5.2 g, 74%).
NMR matched known values. 30
n-BuLi (2.5 M in hexanes, 9.8 mL, 24 mmol) was added dropwise to a cold (-78 'C) slurry of
i-Pr 2NH (3.7 mL, 26 mmol) and LiCL (flame dried under vacuum prior to use) (3.23 g, 77.0
mmol) in THF (17 mL). The suspension was warmed to 0 oC for 5 minutes then cooled to -78
'C. 20 (2.96 g, 12.6 mmol) was added dropwise as a solution in cold (0
oC)
THF (37 mL) and the
reaction stirred at -78 'C for 1 hour, 0 'C for 15 minutes and then room temperature for 5
minutes before being re-cooled to 0 oC. 5-iodo-2-pentyne (1.16 g, 6.00 mmol), available in two
steps from the corresponding alcohol,31 was added in a single portion and the reaction was stirred
at 0 'C for 2 hours before being allowed to gradually warm to room temperature overnight. The
reaction was quenched via the addition of saturated aqueous ammonium chloride and the product
extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered,
concentrated and then purified by silica gel chromatography (3:2 hexanes:ethyl acetate) to give
25 as a viscous pale yellow oil (1.3 g, 73%). The relative stereochemistry of 25 was assigned by
analogy to Myers' work. 29
25 was reduced using LDA and H3B-NH 3 (LAB) prepared as follows:
n-BuLi (2.5 M in
hexanes, 5.3 mL, 13 mmol) was added dropwise to a cold (-78 oC) solution of i-Pr 2NH (2.0 mL,
14 mmol) in THF (14 mL). The solution was warmed to 0 oC and stirred for 10 minutes, then
H3B-NH 3 (410 mg, 13 mmol) was added in a single portion. The reaction was stirred at 0 oC for
an additional 15 minutes and then warmed to room temperature for 15 minutes. The reaction
was re-cooled (0 oC) for the dropwise addition of 25 (1.0 g, 3.3 mmol) in THF (8.3 mL), and
Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119,
6496-6511.
30 Meyers, M. J.; Sun, J.; Carlson, K. E.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 1999, 42,
2456-2468.
31Ansell, M. F.; Emmett, J. C.; Coombs, R. V. J Chem. Soc. C., 1968, 217-224.
29
then warmed back up to room temperature until the reaction was determined to be complete by
TLC (2 hours). The system was cooled to 0 oC and 33 mL of 3 N HCI was added carefully. The
slurry was stirred for 30 minutes at 0 oC, the product was extracted with ether, and the combined
organics washed with 1 N HC1, 1 N NaOH, and brine.
The crude product was dried over
magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (5:2
hexanes:diethyl ether) to give 21 as a clear oil (270 mg, 81%). The enantiomeric excess was
approximated by formation of the Mosher ester of this sample and of racemic material 32 and then
comparing their respective 'H NMR spectra. [a]D -4.6, (c 3.37, CHCl 3, 22
oC);
IR 3348 (b, m),
2961 (s), 2921 (s), 2876 (s), 2361 (m), 2341 (m), 1461 (m), 1380 (w), 1043 (m); 'H NMR (500
MHz, CDC13) 6 3.60 (m, 2H), 2.19 (m, 2H), 1.79 (t, J
=
2.5 Hz, 3H), 1.55 (m, 2H), 1.39 (m, 3H),
0.92 (t, J:= 7.5 Hz, 3H); 13C NMR (125.8 MHz, CDC13)6 79.5, 75.9, 64.9, 41.3, 30.1, 23.4, 16.6,
11.3, 3.7.
2-Ethylhept-5-ynal (22):
0
Me
H
Et
22
DMSO (300 pL, 4.2 mmol) was added to oxalyl chloride (260 iL, 3.0 mmol) in cold (-78 oC)
dichloromethane (20 mL), and the mixture was stirred for 10 minutes before 21 (280 mg, 2
mmol) was added. After stirring for an additional 20 minutes, NEt 3 (840 pL, 6.0 mmol) was
added in a single portion, and the cold bath subsequently removed. The reaction was allowed to
warm for 30 minutes before being quenched via the addition of water.
The product was
extracted with ether and the combined organics dried over magnesium sulfate. The solvent was
removed under reduced pressure (80 torr, 0 'C, rotary evaporator), and the crude mixture was
flushed through a silica plug eluting with 10:1 pentanes:diethyl ether and then concentrated to
give a clear oil (270 mg, 99%). IR 2964 (m), 2923 (m), 2361 (s), 2341 (s), 1726 (m), 1380 (b,
m), 1261 (w); 'H NMR (500 MHz, CDC13) 3 9.64 (d, J= 2.5 Hz, 1H), 2.39 (dtt, Jd = 2.5, Jt =
7.5, 5.5 Hz, 1H), 2.18 (m, 2H), 1.87 (m, 1H), 1.77 (t, J
32
=
2.5 Hz, 3H), 1.70 (m, 1H), 1.66 - 1.52
Racemic material was available using the chemistry of Hodgson and co-workers.
Hodgson, D. M.; Bray, C. D.;
Kindon, N. D. J Am. Chem. Soc. 2004, 126, 6870-6871.
(m, 4H), 0.94 (t, J = 7.5 Hz, 3H); 13C NMR (125.8 MHz, CDC13) 6 205.2, 78.3, 76.9, 52.4, 27.7,
21.7, 16.8, 11.5, 3.6; HRMS m/z (ESI, M + Na ) calcd 161.0937 found 161.0944.
(-)-3-Ethyloct-l-en-6-yne (19):
Me
Et
19
Freshly dried methyltriphenylphosphonium bromide (1.02 g, 2.86 mmol) was added in one
portion to a cooled (0 oC) suspension of K(Ot-Bu) (360 mg, 2.90 mmol) in ether (4 mL),
resulting in the suspension turning bright yellow.
The suspension was warmed to room
temperature and stirred for 40 minutes, 22 (270 mg, 2.0 mmol) was added from a 10 mL pear
shaped flask, rinsing with ether (total volume 2 mL). Stirring was continued for 45 minutes at
room temperature and then the reaction was quenched with water (200 LL). The suspension was
stirred until all of the precipitate collected at the bottom of the flask (5 min) leaving a clear liquid
phase. The flask was equipped with a short-path distillation apparatus and heated to 50 oC to
remove most of the diethyl ether. The receiving flask was then cooled to -78 'C and the system
was placed under vacuum resulting in the instantaneous transfer of all remaining liquid materials
(a mixture of diethyl ether, t-BuOH, water, and 19) to the cooled receiving flask. Sodium sulfate
was added to the biphasic mixture and then the material was passed through a plug of silica
eluting with pentanes. The solvent was removed (0 oC, 140 torr) to give 19 as a clear oil (180
mg, 64%). [a]D -21.1 (c 0.41, CH 2C12, 22 C); IR 3077 (w), 2964 (s), 2921 (s), 2875 (m), 2361
(w), 1640 (w), 1455 (m), 997 (m), 914 (s); 1H NMR (500 MHz, CDC13) 6 5.48 (ddd, J= 17.0,
10.0, 9.5 Hz, 1H), 5.00 (m, 2H), 2.16 (m, 1H), 2.06 (m, 1H), 1.98 (m, 1H), 1.79 (t, J= 2.5 Hz,
3H), 1.60 (m, 1H), 1.40 (m, 2H), 1.26 (m, 1H), 0.86 (t, J= 7.5 Hz, 3H);
13C
NMR (125.8 MHz,
CDC13) 6 142.3, 115.3, 79.5, 75.5, 45.2, 34.1, 27.7, 16.8, 11.8, 3.7; HRMS m/z (EI, M+) calcd
136.1248 found 136.1247.
(-)-8-Ethyl-2,4-dimethyldeca-4,14-dien-3-ol
(23):
I
Me
Et
19
OgH
+ i-PrCHO
Et
Me
Me
Me
23
Following the general procedure for nickel-catalyzed reductive coupling (conditions I) gave
82 mg (78%) of 23 as a single regioisomer and as a mixture of diastereomers (91:1 R, R, to R,
S). Rf = 0.48 (6:1 hexanes:EtOAc, KMnO 4) [U]D -0.45 (c 0.84, CH 2C12, 22 'C); IR 3391 (b, m),
2959 (s), 2922 (s), 2872 (s), 1640 (w), 1460 (m), 1121 (w), 1010 (s), 911 (s);'H NMR (500 MHz,
CDC13) -data is for R, R diastereomer- 6 5.52 (ddd, J = 17.0, 10.0, 9.0 Hz, 1H), 5.34 (t, J = 7.0
Hz, 1H), 5.00 (dd, J= 10.0, 2.0 Hz, 1H), 4.95 (dd, J= 17.0, 2.0 Hz, 1H), 3.57 (dd, J= 9.0, 3.0
Hz, 1H), 2.01 (m, 2H), 1.86 (m, 1H), 1.76 (m, 1H), 1.58 (s, 3H), 1.43 (m, 2H), 1.39 (OH) (d, J=
3.0 Hz, 1H), 1.28 (m, 2H), 0.99 (d, J= 7.0 Hz, 3H), 0.85 (t, J= 7.0 Hz, 3H), 0.78 (d, J= 7.0 Hz,
3H); 13C NMR (125.8 MHz, CDCl 3) 6143.1, 136.5, 128.2, 114.8, 84.5, 45.7, 34.6, 31.3, 28.0,
25.4, 19.7, 18.9, 11.9, 11.4.
The R, S diastereomer was not directly synthesized; however, those peaks which were
resolvable from the R, R diastereomer were: 'H NMR (500 MHz, CDCl 3) 6 5.56 (ddd, J= 17.0,
10.0, 9.0 Hz, 1H), 4.10 (dd, J = 9.0, 3.0 Hz, 1H), 1.07 (d, J= 6.0, 3H), 0.72 (d, J= 6.0 Hz, 3H).
Chapter 1: Spectra
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Chapter 2
Total Synthesis of (+)-Acutiphycin
Introduction
The complex macrolide (+)-acutiphycin (1) was isolated in 1984 by Moore and coworkers and
possesses potent in vivo antineoplastic activity against murine Lewis lung carcinoma, as well as
significant cytotoxicity against KB and NIH/3T3 cell lines.'
Since the natural source of
acutiphycin (the blue-green alga Oscillatoria acutissima) no longer produces this metabolite,
detailed investigations of its mechanism of action and therapeutic potential have been very
limited and further studies must be fueled by chemical synthesis. Smith reported the first total
synthesis of 1 in 1995,2 and a series of studies directed towards the total synthesis of 1 have also
been described by Kiyooka.3 The strategies employed in both the Smith synthesis and the
Kiyooka approach are linear in nature.
Herein, I describe the initial strategy for the total
synthesis of (+)-acutiphycin and the discoveries that resulted from this approach. Additionally a
detailed description of the convergent total synthesis of (+)-acutiphycin is provided.
The nickel-catalyzed reductive coupling of alkynes and aldehydes 4 has been shown to be a
versatile tool in the synthesis of natural products. 5 Although regioselectivity is optimal for arylsubstituted alkynes6 (Scheme 1; eq 1) and 1,3-enynes (eq 2), 7 good levels of regiocontrol have
1 (a) Barchi, J. J., Jr.; Moore, R. E.; Patterson, F. M. L. J. Am. Chem. Soc. 1984, 106, 8193-8197. (b) Moore, R. E.
Pure & Appl. Chem. 1982, 54, 1919-1934.
2
(a) Smith, A. B., III; Chen, S. S.-Y.; Nelson, F. C.; Reichert, J. M.; Salvatore, B. A. J. Am. Chem. Soc. 1995,
117, 12013-12014. (b) Smith, A. B., III; Chen, S. S.-Y.; Nelson, F. C.; Reichert, J. M.; Salvatore, B. A. J. Am.
Chem. Soc. 1997, 119, 10935-10946.
3 (a) Hena, M. A.; Kim, C.-S.; Horiike, M.; Kiyooka, S.-i. Tetrahedron Lett. 1999, 40, 1161-1164. (b) Kiyooka,
S.-i.; Hena, M. A. J. Org. Chem. 1999, 64, 5511-5523.
4 For a review of nickel-catalyzed coupling processes see: Montgomery, J. Angew. Chem. Int. Ed. 2004, 43, 38903908.
5 For representative examples nickel-catalyzed reductive coupling reactions of aldehydes and alkynes in total
synthesis: (a) Synthesis of (+)-allopumiliotoxin 339A: Tang, X. -Q.; Montgomery, J. J Am. Chem. Soc. 1999,
121, 6098-6099. (b) Synthesis of (-)-terpestacin: Chan, J.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 1151411515. (c) Synthesis of (+)-amphidinolide Tl: Colby, E. A.; O'Brien, K. C.; Jamison, T. F. J Am. Chem. Soc.
2004, 126, 998-999.
6 Miller, K. M.; Huang, W.-S.; Jamison, T. F. J Am. Chem. Soc. 2003, 125, 3442-3443.
7 Miller, K. M.; Jamison, T. F. J Am. Chem. Soc. 2004, 126, 15342-15343.
also been observed for alkynes containing two distinct alkyl substituents (eq 3).8 All of these
transformations give exclusive syn addition to the alkyne, resulting in the formation of (E)trisubstituted allylic alcohols, and allows for the possibility of catalyst and/or reagent control.
Scheme 1
Ni(cod) 2 (10 mol%)
(+)-NMDPP (20 mol%)
Et 3 B (200 mol%)
R 1 + R2 CHO
Ar --
OH
Me
R
1
R = alkyl
R 2 = 20 alkyl
R2
Ar ~
-
1
95 : 5 regioselectivity
up to 96% ee
(+)-NMDPP
S"PPh2
i-Pr
R6
R5
R4
+
R
R 7CHO
3
Ni(cod) 2 (10 mol%)
Cyp 3P (20 mol%)
R5
OH
R7
R4
Et3 B (200 mol%)
R3
(2)
R6
6
R = aryl, alkyl (1 , 20, 3")
R3 , R4 , R5 = H, alkyl
>9 0:10 regioselectivity
R7 = aryl, alkyl (10, 20)
S>9
15:5 (E/Z)-selectivity
Ni(cod) 2 (10 mol%)
(S)-FcP(Ph)Me (10 mol%)
O
Cy
--
Me +
H
\i-Pr
Et3B (200 mol%)
=
OH
Cy/
Me'i-Pr
Me
69%, 85 : 15 regioselectivity, 55% ee
In the initial approach to (+)-acutiphycin, I intended to form both of the (E)-trisubstituted
olefins found in the molecule and to establish the configurations at C7 and C13 using these
catalytic processes (Scheme 2).
In addition, due to the challenges associated with
macrolactonization en route to 1,2b I initially investigated an alternative C-C bond-forming
strategy to close the macrocycle: nickel-catalyzed reductive macrocyclization.
8 Colby, E. A.; Jamison, T. F. J Org. Chem. 2003, 68, 156-166.
Although both
reductive coupling reactions were considered to be challenging, the C 13-C 14 bond was targeted
for the ring closing step since the range of oxidation states present along the Cl-C7 backbone
would make it difficult to selectively reveal the C7 aldehyde. An additional disconnection made
at C2-C3 afforded a triply convergent approach, and I envisioned forming this C-C bond via a
Claisen condensation with acetate 6.
Scheme 2
Claiser
conder
fyzed
le coupling
;HO
IYv-cuidiyzel
(+)-acutiphycin (1) reductive cycliz
O
OTBDPS
CHO
MeO
Me
3
9 ,\Me
Me
Me
Me 1O
n-Bu,
Me
15
6
H
OTBS
X
4: X=O
5: X = CH 2
Results and Discussion
The synthesis of the C2-C7 fragment began with enantiomerically enriched 7,9 a well known
intermediate available by alkylation of methyl acetoacetate and subsequent asymmetric reduction
9 Available in two steps from methyl acetoacetate: Eggen, M.; Mossman, C. J.; Buck, S. B.; Nair, S. K.; Bhat, L.;
Ali, S. M.; Reiff, E. A.; Boge, T. C.; Georg, G. 1.J Org. Chem. 2000, 65, 7792-7799.
(Scheme
"' "
3 ).o,
Protection of 7 as the silyl ether followed by reductive debenzylation and
Although hydroxyl groups have been shown to direct addition to
oxidation provided 3.
aldehydes via chelation, 12 a non-chelating protective group, TBDPS, was chosen, since chelation
control via hydroxyl groups has not, to date, been demonstrated in nickel-catalyzed reductive
coupling reactions of alkynes and aldehydes.' 3
Scheme 3
O
OH
MeO
7
95% ee
1. TBDPSCI,
imidazole, DMF
OBn 2. H2, Pd/C, MeOH
3. Dess-Martin
periodinane
O
)II
OTBDPS
CHO
MeO
3
76% (3 steps)
As shown in Scheme 4, enyne 5 (X = CH 2) was selected rather than 4 (X = O) in order to avoid
competitive reductive cyclization during the fragment coupling with 3, as well as other
competing reactions in the Claisen condensation with 6. After the reductive coupling step,
oxidative cleavage of the terminal olefin would reveal the necessary aldehyde functional group.
Additionally, although C i is in the ketone oxidation state in the natural product, the potential
for epimerization2, 3 at C 10 and other complications suggested that the prudent choice would be
to mask C 11 as a protected hydroxyl group. The synthesis of 5 began with an indium-mediated
addition of prenyl bromide to 8, a commonly used derivative of the Roche ester, 14 to give 9
(a) Lee, B. H.; Biswas, A.; Miller, M. J. J. Org. Chem. 1986, 51, 106-109. (b) Huckin, S. N.; Weller, L. Can. J
Chem. 1974, 52, 2157-2164.
" Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1994, p 56.
12 For a review of chelation controlled additions to aldehydes see: Reetz,
M. T. Angew. Chem., Int. Ed. 1984, 23,
556-569.
13 Luanphaisarnnont, T.; Ndubaku, C. O.; Jamison,
T. F. Org. Lett. 2005, 7, 2937-2940.
14 Roush, W. R.; Palkowitz, A. D.; Ando, K. J Am. Chem. Soc. 1990, 112, 6348-6359.
'o
(Scheme 4). 15
The relative stereochemistry was assigned by comparison of the coupling
constants of the benzylidine derivatives of the major and minor diastereomers (Scheme 5).
Protection of the secondary alcohol followed by selective deprotection of the primary alcohol
and the Ley oxidation' 6 provided 10 in good yield over three steps. Treatment of 10 with the
Seyferth-Gilbert reagent' 7 provided a terminal alkyne which was then methylated to yield 5. The
third necessary fragment was available from racemic heptene oxide by way of Jacobsen's
hydrolytic kinetic resolution (Scheme 6).18 Addition of a lithium anion derived from propyne to
11 and subsequent conversion to the acetate ester provided 6.
Scheme 4
Me
Me ,Br,
indium metal
0
OTBS
H
Me
8
9
10
DMF
67%
83:17 syn:anti
OH
SOTBS
Me Me Me
9, >99% ee
1. TBSOTf, 2,6-Lutidine, CH2 C 2
2. CSA, MeOH/CH 2CI 2
3. TPAP, NMO, CH2Cl 2
Me Me Me
73% (3 steps)
10
1. (MeO) 2P(O)CHN 2 , KOt-Bu, THF
2. LDA, DMPU, Mel, THF
81% (2 steps)
CHOOTBS
CHO
S
Me Me Me
5
Arakis, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831-1833. For a recent review of the use of indium
in organic synthesis see: Podlech, J.; Maier, T. C. Synthesis 2003, 633-655.
16 Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J Chem. Soc., Chem. Commun. 1987, 1625-1627.
17 (a) Seyferth, D.; Hilbert, P.; Marmor, R. S. J. Am. Chem. Soc. 1967, 89, 4811-4812. (b) Gilbert, J. C.;
Weerasooriya, U. J. Org. Chem. 1979, 44, 4997-4998.
'8 (a) Tokunaga, M.; Larrow, J. F.; Kakuchi, F.; Jacobsen, E. N. Science, 1997, 277, 936-938. (b) Schaus, S. E.;
Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307-1315.
Scheme 5
JAB
=
JAB
2.2 Hz
HA
9
M
=
9.6 I
H
0
Ph
0
+
syn (major)
anti (minor)
Scheme 6
1. m-CPBA
1-heptene
1. BuLi, propyne,
F3BOEt 2 , THF
n-Bu
2. HKR
vE-
11
33% (2 steps), 99% ee
F,-
2
THE
2. Ac20, NEt 3 ,
DMAP, CH2CI 2
OAc
Me
n-Bu
6
86% (2 steps)
Studies of Nickel-Catalyzed Reductive Fragment Coupling Operations
Based on data obtained in early model studies, 19 it was reasoned that (+)-NMDPP would be an
excellent candidate ligand for stereoselective reductive coupling of 3 and 5 (Table 1, entry 1).
Although the regioselectivity was much greater than expected, 20 the yield in these reactions was
disappointingly low. Moreover, the diastereoselectivity was largely invariant with respect to
ligand, as demonstrated by the fact that, (+)- and (-)-NMDPP and an achiral ligand afforded the
same sense and essentially the same degree of diastereoselectivity (entries 2 and 3). The latter
result was most unexpected and prompted us to test the reaction in the absence of a phosphine
ligand. Not only was this reaction effective, but a significant increase in yield was observed, and
the high degree of regio- and diastereocontrol were maintained (entry 4). At the time, the
success of this coupling stood in stark contrast to all of our previous experience with this
19 The
model
study
featured
1-cyclohexyl-propyne
and
(±)-3-(tert-butyldimethylsilanyloxy)-3phenylpropionaldehyde and gave 77% yield, with 69:31 regioselectivity and 71:29 dr using (+)-NMDPP.
chemistry, in which coupling product in the absence of a phosphine ligand had not previously
been observed.
Table 1: Discovery of an Olefin-Directing Effect in 1,6-Enynes"
,TBDPS
OTBDPS
0CHO
O
MeO
OTBS
Me
+
-
Me Mee
Me
3
_5
entry
1
2
3
4
phosphine
(+)-NMDPP
(-)-NMDPP
P(o-anisyl) 3
none
Ni(cod) 2
phosphine
Et3B
>.5
BS
• .:5 reip•oselctil
yield
39%
45%
52%
84%
drb
80: 20
77 : 23
80 :20
80: 20
" In all cases the reaction was run neat in 350 mol% Et3B using 10 mol% Ni(cod) 2, and (if
employed) 10 mol% phosphine. bDetermined by 'H NMR.
Knochel had previously reported the favorable interaction of a distal alkene in nickel-catalyzed
cross-coupling reactions of alkyl halides with dialkylzinc reagents. 21 Based on this precedent
and our own results, we proposed that the terminal olefin was controlling the regioselectivity of
the reaction by binding to the nickel center. This hypothesis was studied in more detail, and it
has since been determined that the high regioselectivity in phosphine-free nickel-catalyzed
reductive coupling reactions is general for and specific to 1,6-enynes. 22
Unfortunately, the major diastereomer observed in the coupling of 3 and 5 was of the opposite
configuration to that found in 1. As the use of a phosphine additive was detrimental to reaction
20
21
22
The highest selectivity observed with an alkyne featuring a 20 and a 10 terminus is 85:15 (Scheme 1; eq 3), and
frequently lower selectivity is observed. See ref 8.
(a) Devasagayaraj, A.; Stiidemann, T.; Knochel, P. Angew. Chem. Int. Ed. 1995, 34, 2723-2725. (b) Giovannini,
R.; Sttidemann, T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544-3553.
(a) Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342-15343. (b) Moslin, R. M.; Miller, K. M.;
Jamison, T. F. Tetrahedron 2006, 62, 7598-7610.
yield and the possibility of achieving efficient reagent control was limited, I was left to consider
the impact of the stereocenters of 3 and 5. As C11 is a ketone in (+)-acutiphycin I had the luxury
of using epi-C( 11)-5 (13). In order to probe the hypothesis that chiral centers on the 'tether' of a
1,6-enyne might influence the diastereoselectivity in nickel-catalyzed reductive coupling
reactions of aldehydes and 1,6-enynes, I first synthesized model substrate 14 and investigated it
in a reductive coupling with isobutyraldehyde (Scheme 7).23
Scheme 7
i-PrCHO
+
Ni(cod) 2
% Ov
Me
01,ý
Et
14
OH
Et3B
~
Me
0
Et
>95 : 5 regioselectivity
95 : 5 diastereoselectivity
Me
Me1Y
Me
15
Since 15 was isolated as a single regioisomer and 95:5 diastereoselectivity was observed,24 the
reductive coupling study of 14 clearly demonstrated the impact of chiral centers on the tether of
a 1,6-enyne on the stereochemical outcome of coupling reactions. With this result in hand, I
prepared 13, in which the C11 stereocenter on the tether of the 1,6-enyne fragment had been
inverted, using Marshall coupling 25 of aldehyde 1626 and propargylic mesylate 1727 (Scheme 8).
Despite the steric bulk of aldehyde 16, this Marshall coupling proceeded with excellent yield and
enantioselectivity to afford the desired anti product 18 as the only observable diastereomer.
Protection and methylation then provided 13 in six linear steps from tiglic acid.
23 Chapter 1 includes a full discussion of this study and its implications.
The orientation of the aldehyde and mode of diastereoinduction has not been
fully elucidated.
25 Marshall, J. A.; Adams, N. D. J.
Org. Chem. 1999, 64, 5201-5204.
26 Aldehyde 16 is available in 3 steps from tiglic acid via deconjugative methylation. Aurell,
M. J.; Gil, S.; Mestres,
R.; Parra, M.; Parra, L. Tetrahedron 1998, 54, 4357-4366. See Experimental Section.
24
Scheme 8
MeMe
Me Me
HOH
Pd(OAc) 2,
OMs
CHO +
Ph 3P, Et2Zn
Me
16
H
17
1. TBSOTf, Et3 N
CH2C 2
2. LDA, DMPU,
Mel, THF
84% (2 steps)
THF
-78 to C
81% yield
90% ee
>95 : 5 anti : syn
OTBS
Me
Mee
18
Me
Me Me Me
13
Gratifyingly, 13 coupled with 3 in a manner analogous to 5, in this way providing the desired
(S)-allylic alcohol as the major product (Scheme 9). The diastereomeric alcohols were then
converted to their corresponding lactones with PPTS to enable their chromatographic separation
and characterization. 2 8 The strong dependence of diastereoselectivity on the configuration of the
remote C 11 stereocenter provides further evidence of olefin coordination to the metal center. It
is also noteworthy that this coordination appears favorable despite the considerable steric bulk
along the tether of the 1,6-enyne.
27
28
Both enantiomers of 3-butyn-2-ol are commercial available from Aldrich and may also be prepared according to:
Marshall, J. A.; Schaaf, G. M. J. Org. Chem. 2001, 66, 7825-7831.
nOe analysis was used to confirm stereochemical assignment. See Experimental Section for details.
Scheme 9
OTBDPS
19
3+5
Ni(cod) 2
Et3B
>95:5 regioselectiv
PPTS
benzene
600 C
O
\Me
M
O0
H
OTBS
major
84%. 80:20 dr
diastereomer
\
OTBDPS
21
Ni(cod)2
3+13
Et 3 B
>95:5 regioselectivi
PPTS
benzene
0
60C
HC
major
I
650/% 62:f38 dr
\Me
0
"'OTBS
aidstereomer
Consequences of the 1,6-Enyne Approach to (+)-Acutiphycin
Allylic alcohol 20 was carried on to the Claisen condensation as a mixture of diastereomers
(Scheme 10). Fortuitously, the undesired (minor) diastereomer failed to form the hemiketal and
was easily separated from the desired (major) isomer by passing the crude material through a pad
of silica. After methanolysis, compound 22 was obtained as a single diastereomer in 36%
overall yield from 3 and 13.
This route thus afforded the entire carbon skeleton of (+)-
acutiphycin with two consecutive fragment coupling reactions.
Scheme 10
OTBDPS
O
OH O
TBDPS
OH
/TBDPS
O
OH
,,\Me
O
.DA,
n-Bu
diastereomers
major
"OTBS
O'
minoMe
minor
citric acid,
MeOH
n-B
36% from 3/13
(3 steps)
Unfortunately, conversion of the terminal olefin of 22 to the necessary aldehyde proved
extremely challenging, as reaction at the C8-C9 olefin was observed exclusively under
ozonolysis or epoxidation conditions.
Although dihydroxylation was selective for desired
terminal olefin, conversion was very low (<10%). Cleavage of the diol with Pb(OAc) 4 gave a
small amount of the ynal for macrocyclization; however, attempts to form the necessary C-C
bond failed to give any of the desired macrocycle (Table 2).29
29
Hydroacylation was considered because earlier work suggested that aldehydes with a-quaternary centers are
challenging substrates in nickel-catalyzed reductive coupling reactions.
Table 2 Representative Conditions for Cyclization of Ynal
OTBDPS
cyclization conditions
---------------------,
BS
n-B
hydroacylation conditionsa
Ni(cod) 2, P(n-Oct) 3, THF, 100
reductive coupling conditionSb
Ni(cod) 2, PBu 3 , Et 3B, toluene, 80 oCd
OCC
[Rh(dppe)] 2[BF 4] 2, acetone, rt to 80 oC
e
[Rh(dppe)] 2 [BF4]2, acetone, MeCN, rt to 80 oCe
TaC15, Zn, py, benzene, THF, DME, rt to 80
OCf
Ni(cod) 2 , PBu 3, Et2Zn, THF, 0 oC to rtg
(PPh 3)3RhC1, PhNH 2 , 2-amino-3-picoline,
benzoic acid, toluene, 130 to 190 OCh
"To give an a,j3-unsaturated enone.
bTo
give an allylic alcohol. c Ref 30.
d
Ref 5. eRef 31.
1
Ref 32.
gRef 33.
hRef 34.
Although the initial retrosynthetic plan for (+)-acutiphycin did not lead to the completion of
the total synthesis, it revealed the general utility of 1,6-enynes as substrates for highly
regioselective nickel-catalyzed reductive coupling reactions with aldehydes. Additionally, the
phosphine-free nickel-catalyzed reductive coupling of 3 and 13 had successfully provided a
challenging stereocenter and the E-trisubstituted olefin, while also serving as an effective
fragment coupling.
3" Tsuda, T.; Kiyoi, T.; Saegusa, T. J. Org. Chem. 1990, 55, 2554-2558.
3' Tanaka K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 11492-11493.
32 Kataoka, Y.; Miyai, J.; Oshima, K.; Takai, K.; Utimoto, K. J. Org. Chem. 1992, 57, 1973-1981.
33 Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065-9066.
34 Jun, C.-H.; Lee, H.; Hong, J.-B.; Kwon, B.-1. Angew. Chem. Int. Ed. 2002, 41, 2146-2147.
Total Synthesis of (+)-Acutiphycin
The initial approach to (+)-acutiphycin allowed for efficient access to three complex
fragments. In the revised approach, I sought to retain this convergence as much as possible.
However, as the C 13-C 14 bond had proven to be a significant obstacle, I decided to consider the
C14-C15 olefin as an alternate disconnection (Scheme 11).
The C7-C8 disconnection was
retained, and both the C 14-C 15 bond and the ester linkage were considered candidates for ring
closing. The C15-C22 and C3-C7 fragments were largely unchanged from the initial route;
however, the 1,6-enyne now required a ketone functional group and two additional carbons. A
silyl-enol ether (25) was targeted for its potential use in a Mukaiyama aldol strategy.
Scheme 11
OH
ObDu
U
e
Et3SiO
n-Bu
17
CHO
24
MF!
Me
(+)-acutiphycin (1)
O
OTBDPS
5
Et3SiO
Me ,13
O
Et3
CHO
MeO ('
OSiEt 3
1
Me Me Me
3
CHO
Me Me
Me
26
OMs +
25
Me
17
H
Once again, the Marshall coupling served as an excellent means to access homopropargylic
alcohol 27 (Scheme 12). Although I were unaware of any precedent for performing the Marshall
coupling in the presence of a ketone, this approach seemed viable since organozinc species react
significantly more slowly with ketones than with aldehydes. 3 5 Indeed, the P3-keto-aldehyde 2636
proved a viable substrate for these conditions, providing 27 as the anti diastereomer in excellent
yield and enantioselectivity. 37 Protection and methylation afforded 25 in five linear steps from
isobutyraldehyde.
Scheme 12
O
OMs
EtM•CHO
+M
EtMe
Me
e
M
26
1.Et3 SiOTf, Et3N,
CH 2CI 2Me2
17
Pd(OAc) 2 ,
Ph 3P, Et 2Zn
T
O
-O
THe
-78 to0 C
H
OSiEt 3
H
Et
Me Me Me
95% yield
90% ee
>95 :5 anti: syn
Et3SiO
OH
27
Me
2. LDA, DMPU,
Mel, THF
89% (2 steps)
25
Ideally, the enol ether would act similarly to the terminal olefin of 13 in directing
regioselectivity and diastereoselectivity of nickel-catalyzed reductive coupling reactions with 3.
Unfortunately, it was discovered that trisubstituted enol ethers were not suitable directors in
phosphine-free nickel-catalyzed reductive coupling reactions. 38 However, both 25 and 2839
For a review detailing the difficulties associated with asymmetric additions to ketones and the difficulties
associated with this as compared to aldehydes see: Betancort, J. M.; Garcia, C.; Walsh, P. J. Synlett 2004, 749760.
36 Available in two steps from isobutryaldehyde: Shiojii, K.; Kawaoka, H.; Miura, A.; Okuma, K. Synth. Commun.
2001, 31, 3569-3575.
37Determined by X-ray crystallography. For CIF file see: Moslin, R.M.; Jamison, T.F.J. Am. Chem. Soc. 2006,
128, 15106-15107.
38 Compound 24 as well as a TMS, TBS, and acetate-enol ether were all tested with and without a phosphine
additive and in no case was the coupling product observed. Since the reaction was unsuccessful even in the
presence of a phosphine I believe that the enol-ether is coordinated to the nickel center and is either hindering the
approach of the aldehyde sterically or altering the electronics at the nickel such that the reaction cannot proceed.
9 Early work focused on tert-butyl-dimethylsilyl (TBS) protecting groups, although no problems were encountered
with this protecting group, triethylsilyl (TES) protecting group was chosen for later strategies to avoid
anticipated difficulties in deprotection at the C 11 site.
35
could be joined with 3 via the hydrozirconation-transmetallation chemistry of Wipf (Scheme
13). 40 This sequence provided the E-trisubstituted allylic alcohols in excellent regioselectivity as
easily separable mixtures of diastereomers, with the desired (S)-allylic alcohols (23, 29) being
favored. 4 1
A Claisen condensation with 3042 and subsequent methanolysis provided 31.
Oxidation of the primary alcohol to the aldehyde was successful; however, the resultant 3acetoxy aldehyde was prone to elimination, liberating a carboxylic acid.
This sensitivity,
coupled with the stability of the silyl enol ether, prevented the use of a Mukaiyama aldol reaction
to close the macrocycle.
Scheme 13
PO
Me
Me
OP
.
Me Me Me
7
25: 62% yield, 84:16 dr"
28: 77% yield, 73:27 dr
25 P = SiEt 3
28 P = TBS
OTBDPS
Cp 2Zr(H)CI;
Me2Zn, L (20 mol%); 3
Ph
L=
NMe
""Ph
OH
O
O.,\Me
H
23 P = SiEt 3
29 P = TBS
_12 OP
PO0
Me
Me OH
OTBDPS
OAc
n-Bu
OSiEt 3
30
31
1. LDA, 29, THF
SO0
2. Citric acid,
MeOH
OMe H
O -O
n-Bu
75% (2 steps)
,\Me
"OTBS
TBSO
OH
Me
Unanticipated Macrodiolide Formation
40
(a) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197-5200. (b) Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63,
6454-6455.
The Sml2-promoted Reformatsky reaction was considered as a milder way to access the
necessary enolate equivalent. 43 Electrophilic bromination of 31 and subsequent oxidation of the
primary alcohol afforded 32 (Scheme 14). Slow addition of 32 to a dilute solution of SmI2 in
THF at -78 'C resulted in the formation of a new product originally thought to be the desired
macrocycle. However, exposure to Martin sulfurane 44 resulted in the formation of a product
which contained both the characteristic signals of an enone and of a 0-hydroxy ketone in the 'H
NMR. A HRMS determined that the exact mass of this compound was 1711.0651, which
corresponds to the sum of the exact masses of a monomeric macrocyclic enone (846.5286) and a
monomeric macrocyclic P-hydroxy ketone (864.5392). 45 Neither the mass of the monomeric
enone nor the P-hydroxy ketone were observed in the mass spectrum. Consequently, it was
concluded that the SmI2 Reformatsky reaction had produced the macrodiolide (32 membered
ring) and the product obtained after the mono-dehydration was 33.46
This intermolecular-
coupling macrocyclization sequence was unexpected since the preference for intramolecular
addition in Smi2-mediated Reformatsky reactions is well documented.4 3' 4 7
Determined by nOe analysis. See Experimental Section.
Synthesized in a manner analogous to 6. See Experimental Section for details.
43 For a discussion of the advantages of Sm12-mediated Reformatsky reactions including their remarkable
preference to react intramolecularly even in the case of medium-ring lactones see (a): Tabuchi, T.; Kawamura,
K.; Inanaga, J. TetrahedronLett. 1986, 27, 3889-3890. (b) Inanaga, J.; Yokoyama, Y.; Handa, Y.; Yamaguchi,
M. TetrahedronLett. 1991, 32, 6371-6374.
44 Arhart, R. J.; Martin, J. C. J Am. Chem. Soc. 1972, 94, 5003-5010.
45 The M + Na + was recorded on the HRMS, hence the actual value was 1734.0549; however, for ease of
discussion the M' weights are described.
46 33 was not characterized further and its assignment is tentative.
47 For a review of intramolecular Sm12-mediated reactions see: Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem.
Rev. 2004, 104, 3371-3403.
41
42
Scheme 14
OTBDPS
31
1. NBS
1. Sml 2 , THF,
-78 0 C
2. Dess
-Martin [O]
2. Martin
sulfurane
n-B
88%
CHO
Me
P)
Me
Me
33
Macrolactonization Based Strategy
Our focus then shifted to formation of the Cl 4-C 15 olefin via an intermolecular strategy, with
the intention of using macrolactonization to close the ring. Some of these strategies are briefly
summarized by their respective fragments as shown in Scheme 15. The main obstacle in all
these approaches was poor reactivity at the C14 center, due presumably to the steric bulk at
C12.48 Originally it was hoped that the pKa difference between an ester and a ketone would be
sufficient to obtain selective enolate formation at C14. However, when the aldol reaction was
explored with 35 and 36, the C4 protons proved to be more easily abstracted than those at C14,
resulting either in the elimination of the TBDPSO group, or C-C bond formation between C4
and 24 49 . Therefore, strategies such as the Mukaiyama aldol, cross-metathesis, and Zn-mediated
48
49
The failure of many of these techniques is in contrast to the successful application of a variety of aldol reactions
to form a similar P3-hydroxy ketone from an aldehyde and a sterically encumbered ethyl-tert-alkyl ketone in the
synthesis of epothilones. For a recent review of epothilone syntheses see: Watkins, E. B; Chittiboyina, A. G.;
Avery, M. A. Eur.J. Org. Chem. 2006, 4071-4084.
Available in five steps from 1-heptene in a manner similar to that described in Scheme 6. See Experimental
Section.
Reformatsky reactions, which include a built-in bias towards reactivity at C14, were considered.
However, these systems simply proved unreactive and failed to provide any of the desired C-C
bond. The Horner-Wadsworth-Emmons (HWE) strategy was not fully tested because of my
inability to form the necessary j3-keto-phosphonate from 36, probably also due to the steric bulk
at C12.
Scheme 15
OTBDPS
OTBDPS
C3-C14
4
:,\Me
,\Me
Me
'"'/SiEt3
OSiEt 3
Br
H
H
23 P = SiEt 3
29 P =TBS po
c
34 P = TMS
12 "" P
14
Me
0
Et
36
Mukaiyama aldol (with 24)
HWE,
Aldol,
(with 24)
Reformatsky
Aldol (with 24)
OTBDPS
r--------------------------------
0
IC15-C22
~Me
H
"SiEt
3
si7
O3
37
0
Me
Cross-metathesis (with 38)
(also explored ring closing
metathesis)
n-Bu ..
OTES
CHO
17
24
OAc
n-Bu
15
38
An unusual application of the Reformatsky reaction, however, provided an efficient and novel
solution to this problem (Scheme 16). Electrophilic bromination of 23 provided the requisite abromo ketone (36) in quantitative yield. While activated zinc had failed to generate the desired
enolate, 50 SmI2 did so, affording a 3-hydroxy ketone derived from 36 and 24 in excellent yield
(90%, 1.0 mmol scale) as a mixture of diastereomers. Dehydration with the Martin sulfurane
provided 39 in an overall yield of 72% over two steps.
Scheme 16
1. 24, Smi 2
THF
-78 "C
2. Martin
sulfurane,
CH2CI 2
-4 OC
NBS
23 -
99%
36
Me
OTBDPS
O
0
•
e'
H
Et 3SiO
n-Bu
72% (2 steps)
"/OSiEt3
Me
While SmI2 has been commonly employed in intramolecular Reformatsky reactions, its use in
intermolecular cases has been extremely limited due to the numerous side reactions that can
occur.5 1 We propose that the a-quaternary center of 36, which had proved the downfall of the
previous methods, prevents oxidative dimerization of the samarium enolate and other competing
SmI2-mediated pathways. When coupled with subsequent dehydration, this two-step sequence is
complementary to the Horner-Wadsworth-Emmons strategies, and it may find use in other
sterically hindered systems. Further studies to investigate the generality of this approach are
currently underway.
Hydrofluoric acid selectively removed both Et 3Si groups in the presence of the TBDPS group
to afford the P-hydroxyl group necessary for directed reduction (Scheme 17). Formation of the
syn-diol using the most common syn-selective conditions (Et 2BOMe, NaBH 4)52 was completely
unsuccessful in this system; however, the technique developed by Evans utilizing catecholborane
50
In this case, Zn/Ag-graphite was employed: Ftirstner, A. Synthesis 1989, 571-590.
5' Krief, A.; Laval, A.-M. Chem. Rev. 1999, 99, 745-777.
52
Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J. TetrahedronLett. 1987, 28, 155-158.
provided and efficient solution to this problem. 53 The syn-stereochemistry of diol 40 and the
C14-C15 olefin geometry was determined by nOe analysis of the acetonide derivative 41, and
the configuration at C13 was further supported by the
13C
spectra of 41. 54 The only other
examples of a syn-selective reduction of this type, with dimethyl substitution between the
directing alcohol and the carbonyl undergoing reduction, appear to be those of Dixon and
coworkers. 55
Scheme 17
1I.
III,
LFRAM
A
eVI~JI
4U
OTBDPS
39
Me
2. catecholborane
THF
-10 OC
59%
k~L
steps)
MinO OMA
OTBDPS
41
Me
CSA,
acetone
n-Bu
Me
9U3%o
H
nOe
H'5. o
H
OH
n-Bu
,\Me
H
H
7.1%,
Me
H
5.0%
Me
Me
Our early attempts at macrolactonization focused on a strategy similar to that of Smith
(Scheme 18).2
Although the Yamaguchi protocol 56 was successful in formation of the
macrolactone, the mixed anhydride intermediate was very moisture sensitive and consequently
the yield was variable and often very low.
Moreover, elimination of methanol resulted in
formation of 44 as the major product, which could be partially converted to 43 by refluxing in
methanol with citric acid.
However, the rate of conversion was slow, and despite extended
53 Evans, D. A.; Hoveyda, A. H. J. Org. Chem. 1990, 55, 5190-5192.
54 (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945-948. (b) Evans, D. A.; Rieger, D. L.;
Gage, J. R. TetrahedronLett. 1990, 31, 7099-7100.
55 (a) Dixon, D. J.; Scott, M. S.; Luckhurst, C. A. Synlett 2005, 2420-2424. (b) Scott, M. S.; Lucas, A. C.;
Luckhurst, C. A.; Prodger, J. C.; Dixon, D. J. Org. Biomol. Chem. 2006, 4, 1313-1327.
56 Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979,
52, 1989-1993.
reaction times, the reaction did not proceed to completion. Moreover, 43 was not separable from
44 by chromatography.57
Scheme 18
1. 2,4,6-trichlorobenzoyl
chloride, Et3 N, THF
1. EtOAc, LDA
MeOH, citric acid*
2.
40
3. LiOH, H20,
MeOH, THF
2. DMAP, toluene,
110 aC
n-
64% (3 steps)
Yamaguchi protocol
15-65%, 1:4 43:44
MeOH,
citric acid
70 *C
72 h
9:1 mixture
of 43:44
70%
Conversion of 40 to 45 is formally the addition of ketene to the lactone as a nucleophile and
the 20 alcohol as an electrophile (Scheme 19). An alkoxyethyne seemed ideally suited for this
purpose.
Deprotonation of the alkyne terminus would provide an efficient nucleophile, and
alkoxyalkynes are known to undergo thermal decomposition to ketenes, 58 which are potent
electrophiles. 59 The lithium anion of ethoxyethyne (46) smoothly added to the carboxyl at C3 to
give tetraol 47 (Scheme 20). Slow addition of 47 to refluxing xylenes and Bu 3N effected a
thermal retro-ene reaction to form ethylene and ketene 48 that then underwent a highly group-
57 The elimination of methanol to give the ene-ester was also the major product in Smiths synthesis. See ref 2.
58 For an useful discussion of how different alkoxy substitutients affect the temperature at which ethylene is lost
see: Moyano, A.; Pericks, M. A.; Serratosa, F.; Valenti, E. J. Org. Chem. 1987, 52, 5532-5538.
59 Vollema, G.; Arens, J. F. Recl. Trav. Chim. Pays-Bas 1963, 82, 305-321.
selective coupling with the least hindered (yet most remote) of the 4 hydroxyl groups to give the
desired macrocycle (45) in excellent yield (90%).
Scheme 19
OTBDPS
OTBDPS
ttIepuL!U.M
IIIIE;
site
4(
of
45
------------
H2C=C=O
n-Bu
icleophilic
Me
site
n-Bu
OH
H
O
OH H
,\ Me
"/OH
"OH
N
Me
This macrolactonization method was first reported by Funk as a mechanistic probe 60 but had
not been employed previously in the context of total synthesis. 61 As alkynyl ethers lack acidic ahydrogens, they avoid the problem of competing enolate formation that plagues many
macrolactonization techniques. 62
Because of these features, as well as the fact that
macrolactonization is one of the most commonly utilized strategies in complex molecule
synthesis, this retro-ene-macrocyclization certainly warrants further consideration in the field of
natural product synthesis.
Funk, R. L.; Abelman, M. M.; Jellison, K. M. Synlett. 1989, 36-37.
61 We are aware of only two reports of using this technique to form macrolactones: (a) Magriotis, P. A.;
Vourloumis, D.; Scott, M. E.; Tarli, A. Tetrahedron Lett. 1993, 34, 2071-2074. (b) Liang, L.; Ramaseshan, M.;
Magee, D. I. Tetrahedron 1993, 49, 2159-2168.
62 Parenty, A.; Moreau, X.; Campagne, J.-M. Chem.
Rev. 2006, 106, 911-939.
60
Scheme 20
OTBDPS
LiNi-Pr 2
OEt
'
,\Me
0
OH
""OH
"'OH
n-Bu
40
Me
46
H
OH
THF
Bu
72% yield
Me
OTBDPS
47
CH2 =CH 2
Bu3 N, xylenes
150 °C
48
OTBDPS
I
I.
90% yield
n-B
In contrast to 44, methanolysis of 45 proceeded efficiently in 10 hours to give 43 in >99%
yield (Scheme 21).
Selective silylation of the allylic alcohol, Dess-Martin oxidation, 63 and
exposure to HF afforded 49. Crystallization from diethyl ether/pentanes allowed for an X-ray
crystal structure determination of 49 (Figure 1). This is the only known crystal structure of an
acutiphycin derivative and hopefully the structural information obtained from this compound can
63
The ketone product of this reaction was previously synthesized by Smith. See ref 2.
be used to further understand the mode of activity of (+)-acutiphycin. 64 Finally the TBDPS was
removed by treatment with acetic acid-buffered TBAF, 2 completing the total synthesis of (+)acutiphycin (1).
Scheme 21
OTBDPS
45
43
Citric acid,
MeOH
?,\Me
S
OMe H
O
>99%
n-Bu
"'OH
..
'"OH
Me
OTBDPS
1. TESOTf,
2,6-lutidine
2. Dess-Martin
periodinane
3. HF/MeCN
70% (3 steps)
~O
0
/ ·.\Me
OH H
0
TBAF/HOAc
le
0
n-Bu
.,,'OH
Me
n-B
92% yield
(+)-acutiphycin (1)
64
Based on NMR analysis, Moore postulated a solution phase structure of (+)-acutiphycin, which closely matches
the X-ray structure of 49. See ref 1.
Figure 1: X-ray Crystal structure of 49
I
SI
a
-
Ir"
22
Diethyl ether and disorder at the terminus of the C 19-C22 chain omitted for clarity.
Conclusion
Nickel-catalyzed reductive coupling reactions of aldehydes and 1,6-enynes show great
potential for use in total synthesis due to the high regioselectivity, good functional group
tolerance, and substrate-controlled diastereoselectivity. Due to difficulties associated with the
elaboration of the initial retrosynthetic plan, a new highly convergent synthesis of (+)acutiphycin (1) was developed, with a longest linear sequence of 18 steps from either methyl
acetoacetate (4.0%, 84% per step) or isobutyraldehyde (3.1%, 82% per step). Unique features of
this work include the first application of an alkynyl ether as a macrolactone precursor in total
synthesis, and the first use of an intermolecular, SmI2-mediated Reformatsky reaction as a
fragment coupling operation.
The modular nature of the route should enable rapid and
systematic investigation of the structure-activity relationships of this potent natural product.
Experimental Section
General Methods
Unless otherwise noted, all reactions were performed under an oxygen-free atmosphere of
argon using standard Schlenk-line techniques.
Diisopropylamine was distilled from calcium
hydride and stored over potassium hydroxide. Tetrahydrofuran (THF) and diethyl ether were
freshly distilled over sodium/benzophenone ketyl.
toluene were freshly distilled from calcium hydride.
Dichloromethane (DCM), xylenes, and
Ethoxyethyne was received as a red
solution in hexanes from GFS, it was distilled under argon and collected as a clear oil, 1H NMR
was used to determine its weight % in hexanes and it could be stored for up to a month under
argon at -4 'C. All other reagents were used as received unless otherwise noted.
'H NMR was performed on a 500 MHz Varian instrument,
13C
NMR was performed on a 500
MHz Varian instrument equipped with an inverse probe. Deuterochloroform (CDCI 3), which
had been filtered through activated basic alumina prior to use, was used as the solvent. Unless
otherwise noted the reference peak was set to 6 7.27 and 6 77.23 ppm from tetramethylsilane for
the 1H and
13C
spectra respectively. Infrared (IR) spectra were recorded as a thin film between
NaCl plates on a Perkin-Elmer Model 2000 FT-IR System transform spectrometer.
High
resolution mass spectra (HRMS) were obtained on a Bruker Daltonics APEXII 3 Tesla Fourier
Transform Mass Spectrometer by the Massachusetts Institute of Technology Department of
Chemistry Facility.
(+)-5-Benzyloxy-3-(tert-butyldiphenylsilanyloxy)-methyl
O
MeO
pentanoate (50):
OTBDPS
50
OBn
To a cold (0 oC) solution of 79 (8.74 g, 37.0 mmol) in DMF (50 mL) was added imidazole (4.9
g, 72 mmol) and chloro-tert-butyldiphenylsilane(11 mL, 44 mmol), the mixture was warmed to
room temperature and stirred overnight.
The reaction was quenched with water and then
extracted with diethyl ether. The combined organic extracts were washed with water (2x) and
brine, then dried over magnesium sulfate, filtered, concentrated and purified by silica gel
chromatography (50:1 hexanes/diethyl ether -- 6:1 hexanes/ethyl acetate) to give a clear oil.
The oil was placed in a large sublimation apparatus and heated to 70 oC under vacuum (0.01
mmHg) for 24 hours resulting in the collection of an unidentified white solid, recovery of the
residual oil gave 50 (16 g, 90%). [a]D +16.9 (c 1.0, 22 'C, CHC13); chiral HPLC analysis (OD
column, 99:1 hexane:isopropanol 0.7 mL/min) RF (S) = 9.70 min, RF (R) = 10.78 min; IR 3071
(m), 2932 (s), 2858 (s), 1741 (s), 1473 (s), 1428 (s), 1362(s), 1169 (s); 'H NMR (500 MHz,
CDC13) 6 7.68 (m, 4H), 7.40 (m, 4H), 7.30 (m, 4H), 4.37 (quint, J = 6.0 Hz, 1H), 4.33 (s, 2H),
3.53 (s, 3H), 3.49 (m, 1H), 2.53 (d, J = 6.0 Hz, 2H), 1.84 (m, 2H), 1.03 (s, 9H);
13C
(125.8 MHz,
CDC13)0 172.0, 138.5, 136.1, 136.1, 134.0, 129.8, 129.8, 128.5, 127.8, 127.7, 127.7, 127.6, 72.9,
68.5, 66.7, 51.6, 42.4, 37.1, 27.1, 19.5; HRMS m/z (ESI, M+Na +) calcd 499.2275, found
499.2257.
(+)-Methyl 3-(tert-butyldiphenylsilyloxy)-5-oxopentanoate (3):
0
MeO
)
OTBDPS
CHO
3
50 (450 mg, 0.95 mmol) was dissolved in reagent grade methanol (20 mL) and placed in a
high pressure apparatus along with 200 mg of palladium on carbon (10% by weight, 50% water).
The vessel was placed under vacuum (20 mmHg) and backfilled with H2 , this cycle was repeated
twice, and the vessel was charged to 40 psi with H2 and stirred overnight. The reaction solution
was filtered through celite, eluting with ethyl acetate, and concentrated to give the primary
alcohol as a clear oil. The oil was dissolved in CH 2C12 (1.8 mL) and added dropwise to a
solution of Dess-Martin periodinane (810 mg, 1.9 mmol) and pyridine (340 pl, 4.2 mmol) in
CH 2C12 (9 mL) at room temperature. After stirring for 1.5 h, 24 mL of a 1:1 solution of saturated
aqueous sodium bicarbonate and sodium bisulfite was added and the biphasic solution was
stirred until both phases were clear. The layers were separated and the aqueous layer extracted
with diethyl ether. The combined organic layers were washed with saturated aqueous sodium
bicarbonate and brine, dried over magnesium sulfate, filtered, concentrated, and purified by
chromatography (2:1 hexanes/diethyl ether) to give 300 mg (84%) of 3 as a clear oil. [a]D +0.5
(c 1.6, 21 oC, CHCl 3); IR 2895 (s), 2933 (s), 2859 (s), 2361 (m), 1733 (s), 1112 (s), 704 (s); 1H
NMR (500 MHz, CDC13) 6 9.63 (t, J = 2.5 Hz, 1H), 7.67 (m, 4H), 7.46 (m, 2H), 7.40 (m, 4H),
4.62 (quint, J = 6.0 Hz, 1H), 3.58 (s, 3H), 2.69 (ddd, J = 16.5, 6.5, 2.0 Hz, 1H), 2.58 (m, 3H),
1.04 (s, 9H); 13C (125.8 MHz, CDC13) 6 201.0, 171.2, 136.0, 136.0, 133.4, 133.2, 130.2, 130.1,
128.0, 127.9, 66.1, 51.8, 50.6, 42.0, 27.0, 19.4; HRMS m/z (ESI, M+Na +) calcd 407.1649, found
407.1638.
(+)-1-(tert-Butyldimethylsilanyloxy)-2,4,4-trimethylhex-5-en-3-ol
(9):
OTBS
Me Me Me
9
To a cold (0 'C) suspension of indium (4.82 g, 42.0 mmol) in DMF (38 mL) a solution of
aldehyde 814 (3.85 g, 19.1 mmol) and prenyl bromide (6.6 mL, 57 mmol) in DMF (14 mL) were
added in a dropwise fashion. After warming to room temperature and stirring overnight the
reaction was quenched via the addition of 0.5 M HCI (30 mL), the solution was diluted with
diethyl ether, the two layers were separated and the aqueous layer extracted with diethyl ether.
The combined organics were washed with water and brine, dried over magnesium sulfate,
concentrated and crudely purified by chromatography (10:1 hexanes:diethyl ether) to obtain 9 as
a mixture of diastereomers (3.5 g, 83:17 determined by GC).
This material was then re-
subjected to chromatography (25:1 hexanes:diethyl ether) to give 9 as a 96:4 mixture of
diastereomers (2.7 g, >99% ee, 52% yield). Data is for the syn isomer only. [a]D +13.9 (c 0.79,
22 oC, CHCI 3); chiral GC analysis (BDA column, 120 'C, 1.6 mL/min H2) RF (R, S) = 20.8 min,
RF (R, R) = 21.8 min, RF (S, R) = 18.7 min, RF (S, S) = 18.3 min; IR 3510 (bm), 2957 (s), 2930
(s), 2859 (s), 1636 (w), 1472 (m), 1390 (m), 1256 (s), 1093 (s), 1006 (m), 910 (m), 837 (s), 776
(s); 1H NMR (500 MHz, CDC13) ( 5.98 (dd, J= 18.0, 10.5 Hz, 1H), 5.01 (dd, J= 18.0, 1.5 Hz,
1H), 5.01 (dd, J= 10.5, 1.5 Hz, 1H), 3.63 (dd, J= 9.5, 4.0 Hz, 1H), 3.56 (dd, J= 9.5, 5.0 Hz,
2H), 2.52 (d, J= 3.0 Hz, 1H), 1.86 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 0.92 (d, J= 7.0 Hz, 3H),
0.90 (s, 9H), 0.06 (s, 6H);
13C
(125.8 MHz, CDC13) 6 146.2, 111.9, 80.1, 70.4, 41.8, 35.8, 26.1,
24.9, 24.2, 18.4, 11.2, -5.3, -5.4; HRMS m/z (ESI, M+Na +) calcd 295.2064, found 295.2060.
(+)-3-Hydroxy-2,4,4-trimethylhex-5-enal (10):
OTBS
CHO
Me Me Me
10
2,6-Lutidine (3.5 mL, 30 mmol) was added to a solution of 9 (2.72 g, 10.0 mmol) in CH 2Cl 2
(60 mL) and the mixture was cooled to -78 'C. tert-Butyldimethylsilyltriflate (TBSOTf) (3.4
mL, 15 mmol) was added to the cooled solution, which was warmed to 0 oC, stirred for I hour
then quenched with water. The two phases were separated and the aqueous layer extracted with
diethyl ether, the combined organics were washed with water and brine, dried over magnesium
sulfate, filtered, concentrated and purified by silica gel chromatography (hexanes) to give 3.4 g
(88%) of the bis-silyl-ether. A portion of this material (3.2 g, 8.2 mmol) was dissolved in
methanol (220 mL) and CH 2CI 2 (156 mL) and cooled to 0 oC. A solution of CSA (450 mg, 1.9
mmol) in methanol (63 mL) was added and the solution stirred for 4 hours at 0 oC then quenched
with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined
organic layers were washed with 1 M NaOH and brine, dried over magnesium sulfate,
concentrated and purified by silica gel chromatography to give 2.1 g (93%) of the primary
alcohol. To a cold (0 oC) solution of TPAP (140 mg, 0.40 mmol), NMO (2.13 g, 12 mmol), and
powdered 4 A molecular sieves (c. 100 mg) in CH 2C1 2 (40 mL) was added a solution of the
above alcohol (1.1 g, 4.0 mmol) in 16 mL CH 2Cl 2 . The reaction was stirred for 1.5 hours then
passed through a silica pad (eluting with ethyl acetate). The eluent was concentrated purified by
chromatography (6:1 hexanes:diethyl ether) to give 960 mg (89%) of 10. [a]D +17.5 (c 20.57,
22 'C, CHC13); IR 3084 (bm), 2958 (s), 2931 (s), 2859 (s), 1726 (s), 1638 (w), 1473 (s), 1381
(m), 1253 (s), 1142 (m), 1108 (s), 1046 (s), 915 (s), 838 (s), 775 (s), 670 (m); 'H NMR (500
MHz, CDCl13)
9.64 (s, 1H), 5.90 (dd, J= 17.0, 11.5 Hz, 1H), 5.02 (dd, J= 11.5, 1.5 Hz, 1H),
5.01 (dd, J= 17.0, 1.5 Hz, 1H), 4.04 (d, J= 2.0 Hz, 1H), 2.50 (dq, Jq= 7.5, Jd = 2.0 Hz, 1H),
1.15 (d, J= 7.0 Hz, 3H), 1.04 (s, 3H), 1.03 (s, 3H), 0.91 (s, 9H), 0.09 (s, 3H), -0.08 (s, 3H); "C
(125.8 MHz, CDCl 3) 6 205.6, 145.6, 112.6, 75.5, 49.2, 43.2, 26.3, 25.5, 23.1, 18.7, 9.6, -3.4, 4.3; HRMS m/z (ESI, M+Na ) calcd 293.1907, found 293.1907.
(+)-syn-1,6-enyne (5):
OTBS
Me
Me Me Me
5
Potassium tert-butoxide (680 mg, 6.00 mmol) was dissolved in THF (39 mL) and then cooled
to -78 'C, dimethylphosphonodiazomethane (720 mg, 6.0 mmol) was added in THF (13 mL)
dropwise over 15 minutes. After stirring for 15 minutes a solution of 10 (1.02 g, 3.78 mmol) in
THF (13 mL) was added dropwise over 20 minutes. The reaction was stirred at -78 'C for 4
hours, then warmed to room temperature and stirred for an additional 1.5 hours, quenched with
water and extracted with diethyl ether. The combined organic extracts were washed with brine,
dried over magnesium sulfate, concentrated and purified by silica gel chromatography (hexanes)
to give 880 mg (86%) of the terminal alkyne, a portion of which was used in the subsequent step.
n-BuLi (2.5 M in hexanes, 6.1 mL, 15 mmol) was added dropwise to a cold (-10 oC) solution of
iPr 2NH (2.2 mL, 16 mmol) in THF (51 mL) the solution was stirred for 15 minutes, then cooled
to -78 'C. The terminal alkyne (860 mg, 3.2 mmol), DMPU (Aldrich, 3.2 mL, 27 mmol), and
Mel (filtered through activated basic alumina, 0.96 mL, 15 mmol) were added to the solution at 78 'C, the solution was warmed to 0 oC (5 minutes) then to room temperature (2.5 h). The
reaction was quenched via the addition of water, and the product extracted with diethyl ether.
The combined organic layers were washed with brine, dried over magnesium sulfate, filtered,
concentrated and purified by chromatography (hexanes) to give 5 (840 mg, 94%). [a]D +3.1 (c
11.78, 21 oC, CHCl 3); IR 3083 (w), 2959 (s), 2930 (s), 2858 (s), 1638 (w), 1473 (m), 1416 (m),
1360 (m), 1252 (s), 1110 (s), 1035 (s), 913 (s), 834 (s), 774 (s), 671 (m); 1H NMR (500 MHz,
CDC13) &5.94 (dd, J = 18.0, 10.5 Hz, 1H), 4.97 (dd, J = 10.5, 1.5 Hz, 1H), 4.97 (dd, J= 18.0, 1.5
Hz, 1H), 3.61 (d, J= 2.0 Hz, 1H), 2.67 (m, 1H), 1.77 (d, J= 2.5 Hz, 3H), 1.05 (d, J= 7.0 Hz,
3H), 1.01 (s, 3H), 1.00 (s, 3H), 0.95 (s, 9H), 0.18 (s, 3H), 0.10 (s, 3H); 13C (125.8 MHz, CDC13)
5 146.0, 111.6, 85.8, 82.4, 75.8, 43.3, 28.0, 26.5, 25.3, 23.8, 18.8, 16.2, 3.8, -3.0, -4.5; HRMS
m/z (ESI, M+Na ) calcd 303.2115, found 303.2109.
(+)-5-Acetoxydec-2-yne (6):
OAc
n-Bu
6
Me
Propyne was bubbled through a solution of n-BuLi (2.5 M hexanes, 8.0 mL, 20 mmol) was
added to cold (-78
oC)
THF (30 mL) for 10 minutes, at which point (R)- 1,2-heptene-oxide1 '8 65
(1.26 g, 11.0 mmol) was added dropwise, followed by Et20-BF 3 (1.1 mL, 9.0 mmol). The
reaction was stirred at -78 oC for 1.5 hours, quenched with aqueous sodium bicarbonate and
diethyl ether, the two layers were separated and the aqueous layer extracted with diethyl ether.
The combined organics were dried over magnesium sulfate, concentrated and purified by silica
gel chromatography (4:1 hexanes:diethyl ether) to give 1.52 g (94%) of the homopropargylic
alcohol, a portion (690 mg, 4.5 mmol) of which was dissolved in CH 2C12 (9 mL) and cooled to 0
To this was added triethylamine (1.88 mL, 13.5 mmol), acetic anhydride (0.64 mL, 6.8
'C.
mmol) and DMAP (55 mg, 0.45 mmol). The reaction was warmed to room temperature and
stirred for 1.5 hours then quenched with saturated aqueous ammonium chloride. The aqueous
phase was extracted with diethyl ether and the combined organics washed with (saturated
aqueous) sodium bicarbonate, ammonium chloride, and sodium chloride. The organic phase was
dried over magnesium sulfate, concentrated and purified by silica gel chromatography (15:1
hexanes:diethyl ether) to give 810 mg (92%) of 6. [a]D +45.4 (c 0.94, 22 oC, CHCl 3); IR 2957
(s), 2931 (s), 2861 (s), 1740 (s), 1436 (m), 1374 (s), 1239 (s), 1026(s); 'H NMR (500 MHz,
CDC13) 6 4.88 (m, 1H), 2.39 (m, 2H), 2.06 (s, 3H), 1.78 (t, J= 2.5 Hz, 3H), 1.65 (m, 2H), 1.30
(bm, 6H), 0.88 (m, 3H);
13C
(125.8 MHz, CDC13) 5 170.9, 77.8, 74.6, 72.6, 33.2, 31.8, 25.1,
24.4, 22.7, 21.4, 14.2, 3.7; HRMS m/z (ESI, M+Na +) calcd 219.1356, found 219.1357.
2,2-Dimethylbut-3-enal (16):
CHO
CO2 H 1. LiAIH 4
Me Me
51
2. Swern
53% (2 steps)
Me Me
16
A solution of 5126 (6.72 g, 58.9 mmol) in diethyl ether (26 mL) was added dropwise to a
solution of LiA1H 4 (2.05 g, 54.0 mmol) was dissolved in diethyl ether (137 mL), stirred for 2.5
hours then quenched with water. This resulted in the formation of an emulsion which was
dissolved using 5 M HC1. The aqueous layer was extracted with diethyl ether, the combined
organics were washed with water and brine, dried over magnesium sulfate and concentrated (0
oC,
80 torr). The residue was distilled at 0.1 torr, 35-45 'C (receiver flask = -78
65 Gupta, P. S.; Naidu, V.; Kumar, P. TetrahedronLett. 2004, 45, 849-851.
oC)
to give 4.40
g (75%) of the primary alcohol, a portion of which was oxidized to 16. Oxalyl chloride (2.5 mL,
30 mmol) and DMSO (2.84 mL, 40.0 mmol) were added to cold (-78 'C) dichloromethane (100
mL) and the reaction stirred for 20 minutes. A solution of the primary alcohol (2.0 g, 20 mmol)
in 15 mL CH 2C12 was added and the reaction stirred for an additional 30 minutes, followed by
the addition of triethylamine (8.4 mL, 60 mmol). The reaction was warmed to room temperature
and stirred for 2 hours, then quenched via the addition of water. The layers were separated and
the aqueous layer extracted with diethyl ether, the combined organics were washed with 0.5 M
HC1, water, and brine then dried over magnesium sulfate. The solvent was removed under
atmospheric pressure via distillation through a vigreux column (75 °C), THF (4 mL) was used to
rinse the column back into the distillate flask and the majority of the THF was removed via
distillation (95
oC).
The receiver flask was then cooled to -78 'C and 16 was brought over via
vacuum transfer as a solution in THF. The composition of the solution was determined by 'H
NMR to be about 1.4 g of 16 (71%) in 1.3 mL THF (solution p = 0.94 g/mL). 'H NMR (500
MHz, CDCl 3) 5 9.40 (s, 1H), 5.81 (dd, J= 17.5, 10.5 Hz, 1H), 5.21 (d, J
=
10.5 Hz, 1H), 5.15 (d,
J= 17.5 Hz, 1H), 1.20 (s, 6H).
(-)-3,3,5-Trimethylhept-l-en-6-yn-4-ol (18):
OH
H
Me Me Me
18
To a cold (-78 'C) orange solution of Pd(OAc) 2 (5.6 mg, 0.025 mmol) in THF (4 mL) was
added powdered PPh 3 (6.6 mg, 0.025 mmol) and the solution stirred until the PPh 3 dissolved, at
which point the solution turned yellow. (R)-(+)-3-Butyn-2-ol methansulfonate6 6 (96 mg, 0.65
mmol) and 16 (0.5 mmol) were added, followed by dropwise addition of diethylzinc (1 M
hexanes, 1.5 mL, 1.5 mmol) over 15 minutes. The reaction was stirred at -78 'C for 15 minutes
and then placed in an ice bath, which was maintained at 0 oC for 2.5 h, during which time the
reaction solution turned dark. The reaction was quenched via the careful addition of saturated
aqueous ammonium chloride, and then diluted with diethyl ether. The phases were separated
66 Marshall, J. A.; Adams, N. D. J Org. Chem. 2002, 67, 733-740.
and the aqueous layer extracted with diethyl ether. The combined organic layers were washed
with brine and stirred for 20 minutes with magnesium sulfate and decolorizing agent. The slurry
was filtered, concentrated and then purified by silica gel chromatography (12:1 hexanes/diethyl
ether) to give 18 as a clear oil (61 mg, 80%, 90% ee). [a]D -30.1 (c 1.47, 21 'C, CHC13); chiral
GC analysis (BDA column, 60 'C hold 5 min 4 90 'C at 1 oC/min, 0.9 mL/min H2) RF (R, R) =
24.59 min, RF (S, S) = 24.96 min; IR 3550 (bm), 3307 (s), 2975 (s), 2876 (m), 1638 (m), 1452
(m), 1383 (m), 1118 (m), 1051 (m), 978 (s), 917 (s), 632 (s); 'H NMR (500 MHz, CDCI 3) 6 5.91
(dd, J= 17.5, 11.0 Hz, 1H), 5.08 (dd, J
=
11.0, 1.0 Hz, 1H), 5.07 (dd, J= 17.5, 1.0 Hz, 1H), 3.10
(dd, J= 9.5, 1.2 Hz, 1H), 2.80 (qd, Jq= 7.0 Hz, Jd = 1.5 Hz, 1H), 2.20 (d, J= 2.5 Hz, 1H), 1.96
(d, J = 10.0 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.10 (s, 3H), 1.09 (s, 3H);
13
C (125.8 MHz,
CDC13) 6 145.1, 113.5, 85.2, 80.4, 73.3, 42.7, 28.5, 25.0, 22.2, 21.4; HRMS m/z (ESI, M+Na +)
calcd 175.1093, found 175.1092.
(-)-3,3,5-Trimethyl-4-(tert-butyldimethylsilyloxy)-hept-l-en-6-yn
OTBS
(52):
H
Me Me Me
52
tert-Butyldimethylsilyltriflate (TBSOTf) (1.1 mL, 5.2 mmol) was added to a cold (-78
oC)
solution of 18 (240 mg, 1.6 mmol) and 2,6-lutidine (1.1 mL, 9.4 mmol) in dichloromethane (10
mL), and the solution was warmed to room temperature overnight. Water and diethyl ether were
added to the reaction, the aqueous layer was extracted with diethyl ether and the combined
organic layers were washed with brine, dried over magnesium sulfate, concentrated, and purified
by chromatography (hexanes) to give 370 mg (89%) of 52 as a clear oil. [D]o -6.0 (c 0.29, 21
"C, CHCI3); IR 3314 (s), 3084 (w), 2960 (s), 2858 (s), 1640 (w), 1473 (s), 1415 (m), 1361 (s),
1253 (s), 1130 (s), 1091 (s), 1017 (s), 916 (s), 862 (s), 837 (s), 773 (s), 631 (s); 1H NMR (500
MHz, CDC13)6 5.91 (dd, J= 17.5, 10.5 Hz, 1H), 5.02 (dd, J= 17.5, 1.5 Hz, 1H), 4.99 (dd, J=
10.5, 1.5 Hz, 1H), 3.24 (d, J
=
1.0 Hz, 1H), 2.76 (ddq, Jq = 7.5 Hz, Jd = 2.5, 1.0 Hz, 1H), 2.03 (d,
J= 2.5 Hz, 1H), 1.22 (d, J= 7.5 Hz, 3H), 1.09 (s, 3H), 1.05 (s, 3H), 0.96 (s, 9H), 0.12 (s, 3H),
0.08 (s, 3H); 13 C (125.8 MHz, CDC13) ( 146.4, 112.0, 86.9, 82.0, 71.0, 43.5, 29.4, 26.4, 25.8,
22.4, 21.4, 18.9, -3.1, -3.5; HRMS m/z (ESI, M+Na ÷) calcd 289.1958, found 289.1958.
(-)-anti-1,6-Enyne (13):
OTBS
Me
Me Me Me
13
n-BuLi (2.5 M in hexanes, 2.6 mL, 6.5 mmol) was added dropwise to a cold (-10 oC) solution
of iPr 2NH (0.95 mL, 6.8 mmol) in THF (21 mL) the solution was stirred for 15 minutes, then
cooled to -78 oC.
52 (360 mg, 1.35 mmol), DMPU (Aldrich, 1.4 mL, 12 mmol), and Mel
(filtered through activated basic alumina, 0.40 mL, 6.5 mmol) were added to the solution at -78
oC,
the solution was warmed to 0 oC (5 minutes) then to room temperature (2.5 h). The reaction
was quenched via the addition of water, and the product extracted with diethyl ether. The
combined organic layers were washed with brine, dried over magnesium sulfate, filtered,
concentrated and purified by silica gel chromatography (hexanes) to give 13 (360 mg, 95%).
[a]D -0.44 (c 0.90, 22 'C, CHCl 3); IR 2959(s), 2859 (s), 1639 (w), 1473 (s), 1361 (s), 1255 (s),
1056 (s), 999 (s), 857 (s), 835 (s), 774 (s); 1H NMR (500 MHz, CDC13) 6 5.92 (dd, J= 17.5, 11.0
Hz, 1H), 4.99 (dd, J= 17.4, 1.5 Hz, 1H), 4.96 (dd, J= 11.0, 1.5 Hz, 1H), 3.21 (d, J = 1.5 Hz,
1H), 2.67 (m, 1H), 1.76 (d, J= 2.5 Hz, 3H), 1.16 (d, J= 7.5 Hz, 3H), 1.06 (s, 3H), 1.03 (s, 3H),
0.96 (s, 9H), 0.11 (s, 3H), 0.07 (s, 3H); 3C (125.8 MHz, CDCl 3) 6 146.7, 111.5, 82.3, 81.7, 77.9,
43.4, 29.6, 26.3, 25.6, 22.7, 21.6, 18.8, 3.8, -3.3, -3.5; HRMS m/z (ESI, M+Na +) calcd
303.2115, found 303.2115.
Nickel-catalyzed reductive coupling of 3 with 5/13:
0
Ni(cod) 2
3+
Phosphine
/TBDPS
0
OH
M,
Et3B
no inomint-H ,
Representativeprocedure (3 + 5 with no phosphine additive):
In a glovebox, Ni(cod) 2 (5.5 mg, 0.020 mmol, 10 mol%) was added to a pre-dried 25 mL
round bottom flask, if phosphine was included it was added (10 mol%) at this time (in this
example it was not). The flask was then placed under argon on a Schlenk line and neat Et 3B was
added (0.10 mL, 0.69 mmol, 345 mol%). The solution was cooled to 0 oC and 3 (76 mg, 0.20
mmol, 100 mol%) was added followed by the 1,6-enyne (5) (58 mg, 0.20 mmol, 102 mol%).
The reaction was stirred for I hour at 0 'C and then warmed to room temperature and stirred for
3 additional hours. The reaction was diluted with reagent grade EtOAc, opened to the
atmosphere and stirred for 30 minutes. Solvent was removed in vacuo and crude material was
purified via silica gel purified by silica gel chromatography (50:1 hexanes:diethyl ether -- 7:2
hexanes:diethyl ether) to give 110 mg (84%) of 12 as a mixture of diastereomers (c. 80:20 C7
R:S).
A similar procedure (1 mmol scale) was performed for 3 + 13, giving 440 mg (65%) of 20 as a
mixture of diastereomers (c. 62:38 C7 S:R).
6-Lactones (19, 53, 21, 54):
S
2.9%
11.7%
.,,H
O
O
H
0\Me O1
H
\
1..H
H
,\Me
O\
H
H
\
14.5%
1.,H
<0.5%
,\Me
.O ,
"-"OTBS
"'OTBS
OTBS
53
10.8%
H
,,\Me
OTBS
19
4.5%
10.2%
H
H
OTBDPS
OTBDPS
OTBDPS
OTBDPS
<0.05% 1..\H
21
54
Since the diastereomers could not be separated they were characterized as their 6-lactones.
The following is a representative procedure: PPTS (1 mg, 0.004 mmol) was added to a solution
of 12 (15 mg, 0.022 mmol) in benzene (1.5 mL), the vessel was sealed and heated to 60 oC for 2
hours, the solvent was removed in vacuo and the crude material purified by silica gel
chromatography (10:1 hexanes:diethyl ether) to give 11 mg (79%) of 19 (more polar) and 2.7 mg
(19%) of 53 (less polar). Spectral data is provided for all four 6-lactones:
19:
[at]D +1.2 (c 1.46, 21 'C, CHCl 3); IR 2959 (s), 2931 (s), 2858 (s), 1742 (s), 1472 (m), 1428
(m), 1380 (w), 1236 (m), 1112 (s), 1080 (s), 1028 (s), 911 (w), 834 (m), 702 (s); 'H NMR (500
MHz, CDC13) 6 7.64 (m, 4H), 7.47 (m, 2H), 7.40 (m, 4H), 5.91 (dd, J= 17.6, 10.9 Hz, 1H), 5.51
(nOe 11.7%) (d, J= 9.9 Hz, 1H), 5.16 (nOe 11.7%) (dd, J= 10.6, 3.5 Hz, 1H), 4.97 (dd, J=
17.6, 1.4 Hz, 1H), 4.95 (dd, J= 10.9, 1.4 Hz, 1H), 4.30 (m, 1H), 3.26 (d, J= 2.0 Hz, IH), 2.64
(m, 1H), 2.60 (dt, Jt = 2.4, Jd = 18.0 Hz, 1H), 2.45 (dd, J
=
13.3, 4.5 Hz, 1H), 1.75 (m, 2H), 1.55
(d, J= 1.0 Hz, 3H), 1.09 (s, 9H), 1.01 (s, 3H), 1.00 (s, 3H), 0.95 (s, 9H), 0.91 (d, J= 6.5 Hz, 3H),
0.07 (s, 6H);
13C
(125.8 MHz, CDC13) 6 170.5, 146.5, 136.1, 135.8, 135.8, 133.3, 133.3, 130.3,
130.3, 129.6, 128.1, 128.1, 111.3, 82.6, 81.6, 64.6, 43.4, 39.0, 34.7, 34.4, 27.1, 26.5, 25.7, 23.8,
19.3, 18.9, 15.8, 11.9, -2.6, -3.6; HRMS m/z (ESI, M+H +) calcd 635.3946, found 635.3968.
53:
[a]D +4.6 (c 0.19, 21 'C, CHC13); IR 2959 (s), 2931 (s), 2858 (s), 1744 (s), 1472 (m), 1428
(m), 1380 (m), 1252 (m), 1106 (s), 1027 (s), 834 (m), 773 (m), 702 (s); 'H NMR (500 MHz,
CDC13) 6 7.66 (m, 4H), 7.47 (m, 2H), 7.41 (m, 4H), 5.90 (dd, J= 17.5, 10.9 Hz, 1H), 5.36 (nOe
10.2%) (d, J= 9.8 Hz, 1H), 4.98 (dd, J= 17.5, 1.4 Hz, 1H), 4.96 (dd, J= 10.9, 1.4 Hz, 1H), 4.27
(nOe 10.2%, 2.9%) (dd, J = 11.9, 3.0 Hz, 1H), 4.12 (nOe 2.9%) (m, 1H), 3.28 (d, J = 1.9 Hz,
1H), 2.71 (ddd, J= 17.2, 5.8, 1.3 Hz, 1H), 2.62 (m, 1H), 2.49 (dd, J= 17.3, 8.3 Hz, 1H), 1.93 (m,
1H), 1.84 (m, 1H),1.58 (d, J= 1.0 Hz, 3H), 1.07 (s, 9H), 1.00 (s, 3H), 0.98 (s, 3H), 0.94 (s, 9H),
0.86 (d, J= 6.5 Hz, 3H), 0.04 (s, 3H), 0.03 (s, 3H);
3C
(125.8 MHz, CDC13) ( 171.0, 146.5,
136.3, 135.9, 133.6, 133.3, 130.2, 130.2, 129.3, 128.1, 128.0, 111.4, 82.5, 82.2, 65.7, 43.5, 40.1,
37.4, 34.2, 27.0, 26.6, 25.6, 23.7, 19.2, 18.9, 15.7, 11.7, -2.5, -3.7; HRMS m/z (ESI, M+H +)
calcd 635.3946, found 635.3962.
21:
[a]D +22.4 (c 0.87, 21 oC, CHC13); IR 2959 (s), 2931 (s), 2858 (s), 1742 (s), 1472 (m), 1428
(s), 1380 (m), 1253 (s), 1107 (s), 1036 (s), 911 (s), 834 (s), 736 (s), 702 (s); 'H NMR (500 MHz,
CDC13) 6 7.66 (m, 4H), 7.46 (m, 2H), 7.40 (m, 4H), 5.79 (dd, J= 17.5, 10.9 Hz, 1H), 5.65 (nOe
10.8%) (d, J= 9.4 Hz, IH), 4.92 (dd, J= 17.5, 1.4 Hz, 1H), 4.89 (dd, J= 10.9, 1.4 Hz, 1H), 4.27
(nOe 10.2%, 4.5%) (dd, J = 11.9, 3.0 Hz, 1H), 4.12 (nOe 4.5%) (m, 1H), 3.35 (d, J= 0.6 Hz,
1H), 2.72 (ddd, J = 17.3, 5.9, 1.3 Hz, 1H), 2.67 (quint, J= 7.5 Hz, 1H), 2.49 (dd, J = 17.3, 8.3
Hz, 1H), 1.91 (m, 1H), 1.84 (m, 1H),1.58 (d, J= 1.0 Hz, 3H), 1.07 (s, 9H), 0.95 (s, 9H), 0.94 (s,
3H), 0.92 (d, J= 7.5 Hz, 3H), 0.90 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H); 13 C (125.8 MHz, CDC13) (
171.1, 146.7, 135.9, 133.6, 133.4, 132.2, 130.3, 130.2, 129.2, 128.1, 128.0, 111.4, 84.1, 82.4,
65.7, 43.2, 40.1, 37.3, 34.5, 27.0, 26.6, 26.2, 22.5, 21.2, 19.2, 19.0, 12.2, -2.8, -3.2; HRMS m/z
(ESI, M+H +) caled 635.3946, found 635.3961.
54:
[a]D +5.9 (c 0.38, 22 TC, CHC13); IR 2959 (s), 2930 (s), 2858 (s), 1739 (s), 1472 (m), 1428
(m), 1235 (s), 1111 (s), 1037 (s), 870 (m), 773 (m), 702 (s); 'H NMR (500 MHz, CDC13) 6 7.64
(m, 4H), 7.46 (m, 2H), 7.40 (m, 4H), 5.84 (dd, J
=
17.6, 10.7 Hz, 1H), 5.79 (nOe 14.5%) (d, J=
9.4 Hz, 1H), 5.24 (nOe 14.5%) (dd, J = 9.9, 5.5 Hz, 1H), 4.96 (dd, J= 17.6, 1.1 Hz, IH), 4.84
(dd, J= 10.7, 1.1 Hz, 1H), 4.28 (m, 1H), 3.37 (s, 1H), 2.65 (m, 1H), 2.45 (dd, J= 17.6, 4.3 Hz,
1H), 1.68 (m, 2H), 1.53 (s, 3H), 1.08 (s, 9H), 0.99 (d, J = 7.0 Hz, 3H), 0.96 (s, 9H), 0.96 (m,
3H), 0.91 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H); ' 3C (125.8 MHz, CDC13) 6 170.7, 146.7, 135.9,
135.8, 133.4, 132.6, 130.3, 130.2, 129.3, 128.5, 128.1, 128.1, 111.0, 84.3, 82.6, 64.7, 43.2, 39.0,
34.5, 34.0, 27.1, 26.7, 26.0, 23.2, 21.2, 19.3, 19.1, 11.4, -2.8, -3.2; HRMS m/z (ESI, M+H+)
calcd 635.3946, found 635.3967.
(+)-Enyne (22):
OTBDPS
n-E
n-BuLi (2.5 M in hexanes, 490 pL, 1.2 mmol) was added to a cold (-10 'C) solution of iPr 2NH
(170 jiL, 1.2 mmol) in THF (3 mL) the solution was stirred for 15 minutes, then cooled to -42
'C. A solution of 6 (240 mg, 1.2 mmol) in THF (1 mL) was added dropwise and the solution
stirred for 45 minutes, followed by the dropwise addition of 20 (c. 62:38 mixture of
diastereomers, 220 mg, 0.33 mmol) in THF (2 mL). After 4 hours at -42 TC the reaction was
quenched via the addition of water and diethyl ether. The layers were separated and the aqueous
layer extracted with diethyl ether. The combined organic layers were washed with 0.5 M HC1,
water, and brine then dried over magnesium sulfate and concentrated. The crude material was
flushed through a plug of silica eluting with 10:1 hexanes:diethyl ether leaving a clear oil. This
crude material was dissolved in 7 mL of methanol and heated to 65 'C for 2 hours with citric
acid (100 mg, 0.48 mmol), the methanol was removed in vacuo and the residue purified by silica
gel chromatography (30:1 hexanes:ethyl acetate) to give a clear oil. The oil was warmed to 50
'C and placed under vacuum (0.04 torr) overnight to remove excess 6, resulting in 160 mg (57%)
of 22 (>95:5 dr). [a]D +32.8 (c 0.57, 22 oC, CHCI 3); IR 3584 (m), 2956 (s), 2930 (s), 2858 (s),
1737 (s), 1472 (m), 1428 (m), 1378 (m), 1251 (m), 1112 (s), 1042 (s), 834 (m), 702 (s); 1H NMR
(500 MHz, CDCI 3) 6 7.66 (m, 4H), 7.41 (m, 2H), 7.37 (m, 4H), 5.81 (dd, J
=
17.5, 10.5 Hz, 1H),
5.53 (d, J = 9.5 Hz, 1H), 4.87 (m, 3H), 4.14 (m, 1H) 3.58 (d, J= 11.0 Hz, 1H), 3.33 (s, 1H), 2.73
(d, J=13.5 Hz, 1H), 2.61 (m, 1H), 2.54 (d, J= 13.5 Hz, 1H), 2.37 (m, 2H), 2.26 (dd, J= 13.0,
4.0 Hz, 1H), 1.77 (t, J= 2.5 Hz, 3H), 1.69 (m, 2H), 1.49 (s, 3H), 1.42 (q, J= 12.0 Hz, 1H), 1.361.24 (m, 9H), 1.05 (s, 9H), 0.94 (s, 9H), 0.94 (m, 3H), 0.89 (m, I1H), 0.09 (s, 3H), 0.08 (s, 3H);
'3 C (125.8 MHz, CDC13)6 169.1, 147.0, 136.0, 136.0, 134.8, 134.6, 131.5, 129.7, 129.4, 127.7,
127.7, 111.0, 99.6, 84.3, 77.8, 74.7, 74.2, 72.7, 67.0, 47.8, 43.2, 43.0, 42.6, 38.8, 34.4, 33.1, 31.8,
27.2, 26.6, 26.1, 25.0, 24.2, 22.8, 22.7, 21.3, 19.3, 19.0, 14.2, 12.9, 3.8, -2.8, -3.2; HRMS m/z
(ESI, M+Na +) calcd 867.5386, found 867.5473.
(-)-5-Hydroxy-4,4,6-trimethyloct-7-yn-3-one
O
(27):
H
OH
Et
Me Me Me
"7
To a cold (-78
oC)
orange solution of Pd(OAc) 2 (65 mg, 0.29 mmol) in THF (120 mL) was
added powdered PPh 3 (76 mg, 0.29 mmol) and the solution stirred until it dissolved, at which
point the solution turned yellow. (R)-(+)-3-Butyn-2-ol methansulfonate 66 (3.0 g, 20 mmol) and
2,2-dimethyl-3-pentanon-al 36 (1.99 g, 15.5 mmol) were added, followed by dropwise addition of
diethylzinc (1 M hexanes, 58 mL, 58 mmol) over 15 minutes. The reaction was stirred at -78 'C
for 15 minutes and then placed in an ice bath, which was maintained at 0 oC for 2.5 h, during
which time the reaction solution turned dark. The reaction was quenched via the careful addition
of saturated aqueous ammonium chloride, and then diluted with diethyl ether. The phases were
separated and the aqueous layer extracted with diethyl ether. The combined organic layers were
washed with brine and stirred for 20 minutes with magnesium sulfate and decolorizing agent.
The slurry was filtered, concentrated and then purified by silica gel chromatography (3:1
hexanes/diethyl ether) to give a clear oil which crystallized upon standing (2.7 g, 95%, >95:5 dr,
90% ee). Relative stereochemistry of 27 was determined by X-ray crystallography. [a]D -1 1.1 (C
0.81, 21 'C, CHC13); chiral GC analysis (P3-PH column, 88 'C, 1.5 mL/min H2) RT (S, S) = 46.85
min, RT (R, R) = 47.91 min; IR 3415 (bs), 3265 (s), 2975 (s), 1681 (s), 1386 (m), 972 (m); 1H
NMR (500 MHz, CDC13)6 3.50 (dd, J = 9.0, 2.0 Hz, 1H), 3.35 (d, J = 9.0 Hz, 1H), 2.70 (m,
1H), 2.65 (dq, Jd= 18.5, Jq = 7.0 Hz, 1H), 2.54 (dq, Jd
=
18.5, Jq = 7 .0 Hz, 1H), 2.14 (d, J = 2.0
Hz, 1H), 1.32 (d, J = 7.0 Hz, 3H), 1.27 (s, 3H), 1.22 (s, 3H), 1.02 (t, J = 7.0 Hz, 3H);
13
C (125.8
MHz, CDC13) 5 218.1, 84.9, 73.0, 51.1, 32.4, 28.9, 23.5, 21.5, 20.4, 7.8; HRMS m/z (ESI,
M+Na +) calcd 205.1205, found 205.1195.
(+)-3,5,5-Trimethyl-4,6-bis-triethylsilanyloxy-oct-5-en-1-yne
TESO
Me
OTES
(55):
H
Me Me Me
55
To a cold (-78
oC)
solution of 27 (1.13 g, 6.2 mmol) and NEt 3 (4.3 mL, 31 mmol) in CH 2CI 2
(12 mL) was added triethylsilyltriflate (TESOTf) (5.6 mL, 25 mmol), the reaction was warmed
to room temperature and stirred overnight. The reaction was quenched with saturated sodium
bicarbonate and diluted with diethyl ether, the layers were separated and the organic layer was
washed with brine, dried over magnesium sulfate, filtered, concentrated and purified by silica gel
chromatography (hexanes) to give 55 as a clear oil (2.5 g, 98%). [a]D +9.4 (c 4.08, 21 'C,
CHCl 3); IR 3314 (m), 2956 (s), 2878 (s), 1664 (m), 1459 (m), 1317 (m), 1240 (m), 1136 (s),
1008 (s), 738 (s); 1H NMR (500 MHz, CDC13)6 4.65 (q, J = 7.0 Hz, 1H), 3.66 (d, J = 1.0 Hz,
1H), 2.72 (ddq, Jq = 7.0, Jd = 2.5, 1.5 Hz, 1H), 2.00 (d, J = 2.5 Hz, 1H), 1.52 (d, J = 7.0 Hz, 3H),
1.22 (d, J = 7.0 Hz, 3H), 1.09 (s, 3H), 1.06 (s, 3H), 1.01 (t, J = 8.0 Hz, 9H), 1.00 (t, J = 8.0 Hz,
9H), 0.73 (q, J = 8.0 Hz, 6H), 0.66 (apparent dt, Jt = 8.0, Jd = 1.5 Hz, 6H);
13C
(125.8 MHz,
CDC13) ( 157.2, 99.5, 87.5, 79.4, 70.4, 46.5, 28.9, 25.4, 21.9, 20.3, 11.7, 7.4, 7.2, 6.4, 5.9;
HRMS m/z (ESI, M+Na +) calcd 433.2929, found 433.2911.
(+)-4,6,6-Trimethyl-5,7-bis-triethylsilanyloxy-non-7-en-2-yne
(25):
TESO
OTES
Me
5
Me
Me Me Me
25
n-BuLi (2.5 M in hexanes, 11 mL, 27 mmol) was added dropwise to a cold (-10 'C) solution
of iPr 2NH (4.0 mL, 28 mmol) in THF (100 mL) the solution was stirred for 15 minutes, then
cooled to -78 'C. 55 (2.42 g, 5.88 mmol), DMPU (Aldrich, 5.9 mL, 49 mmol), and Mel (filtered
through activated basic alumina, 1.8 mL, 28 mmol) were added to the solution at -78 oC, the
solution was warmed to 0 oC (5 minutes) then to room temperature (2.5 h). The reaction was
quenched via the addition of water, and the product extracted with diethyl ether. The combined
organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated and
purified by chromatography (hexanes) to give 25 (2.3 g, 91%). [a]D +11.0 (c 3.1, 21 oC, CHCI3);
IR 2956 (s), 2916 (s), 2878 (s), 2361 (w), 1664 (m), 1458 (m), 1317 (m), 1116 (s), 1004 (s), 845
(m),737 (s); 'H NMR (500 MHz, CDC13) 6 4.62 (q, J = 6.5 Hz, 1H), 3.63 (d, J = 1.5 Hz, 1H),
2.63 (m,1H), 1.76 (d, J = 2.0 Hz, 1H), 1.50 (d, J = 7.0 Hz, 3H), 1.16 (d, J = 7.5 Hz, 3H), 1.06
(s, 3H), 1.05 (s, 3H), 1.00 (t, J = 8.0 Hz, 9H), 1.00 (t, J = 8.0 Hz, 9H), 0.72 (q, J = 8.0 Hz, 6H),
0.64 (q, J = 8.0, 6H); 13C (125.8 MHz, CDC13) 5 157.4, 99.3, 82.2, 79.6, 77.3, 46.4, 29.0, 25.3,
22.2, 20.4, 11.7, 7.3, 7.2, 6.4, 5.9, 3.9; HRMS m/z (ESI, M+Na ÷) calcd 447.3085, found
447.3076.
(+)-Lactones (23, 29):
OTBDPS
.
-.
H
7. %
"\\
H
9.4%
O
OTBDPS
145%
4%H
H
4.4%
,\O
\Me
O
H
"'"OTES
TESO N
23
\Me
"'OTBS
TBSO
Me
29
Me
Representative procedure for coupling (23):
In a darkened fume hood a solution of
Cp 2Zr(H)Cl (690 mg, 2.7 mmol) and 25 (1.10 g, 2.60 mmol) in toluene (20 mL) was heated to 43
'C for 80 minutes then cooled to -65 'C. Dimethylzinc (2 M in toluene, 1.3 mL, 2.6 mmol) was
slowly added to the cold solution followed by a,a-diphenyl-N-methyl-D-prolinol (110 mg, 0.40
mmol). The reaction was allowed to gradually warm up to -30 oC over 90 minutes, at which
point 3 (770 mg, 2.0 mmol) in 5 mL toluene was added followed by a 3 mL rinse (toluene). The
reaction was warmed to -25 'C and stirred for 50 minutes then warmed to -15 oC and stirred
overnight. The reaction was warmed to room temperature then heated to 35 oC for 20 minutes,
this was done to ensure complete conversion to the lactone. The reaction was cooled to 0 oC and
quenched via the careful addition of saturated aqueous ammonium chloride. The aqueous layer
was extracted with diethyl ether and the combined organics were washed with 0.1 M NaHSO 4
and brine, dried over magnesium sulfate, filtered, concentrated and subject to chromatography:
50:1 hexanes/diethyl ether, 80 mL (removes excess 25 and related) -4 9:1 hexanes/diethyl ether,
1 L (23) 4 6:1 hexanes/diethyl ether (epi-C(7)-23), to give 810 mg 23 (52%) and 154 mg epiC(7)-23 (10%) as clear oils (data for 23 only). [a]D +16.0 (c 1.85, 22 oC, CHCI3); IR 2957 (s),
2877 (s), 1747 (s), 1664 (w), 1460 (w), 1381 (w), 1317 (w), 1231 (m), 1111 (s), 1008 (s), 738
(s); 1H NMR (500 MHz, CDC13) 6 7.65 (m, 4H), 7.46 (m, 2H), 7.40 (m, 4H), 5.63 (nOe 14.5%)
(d, J = 9.5 Hz, 1H), 4.51 (q, J = 6.5 Hz, 1H), 4.31 (nOe 14.5%, 9.4%) (dd, J = 6.5, 3.5 Hz, 1H),
4.12 (nOe 9.4%) (m, 1H), 3.77 (s, 1H), 2.70 (ddd, J = 17.0, 6.0, 1.0 Hz, 1H), 2.62 (m, 1H), 2.49
(dd, J = 17.0, 8.0 Hz, 1H), 1.87 (m, 2H), 1.55 (d, J = 1.0 Hz, 3H), 1.50 (d, J = 6.5 Hz, 3H), 1.07
(s, 9H), 1.03-0.96 (m, 21 H), 0.89 (d, J = 7.0 Hz, 3H), 0.82 (s, 3H), 0.73 (q, J = 8.0 Hz, 6H),
0.64 (q, J = 8.0 Hz, 6 H);
13
C (125.8 MHz, CDC13) 6 171.3, 157.4, 135.9, 133.7, 133.4, 133.0,
130.3, 130.2, 128.9, 128.1, 128.0, 99.1, 82.9, 81.2, 77.2, 65.7, 46.1, 40.1, 37.4, 34.2, 27.0, 25.7,
21.2, 20.6, 19.2, 11.6, 7.5, 7.2, 6.4, 5.9; HRMS m/z (ESI, M+Na ÷) calcd 801.4738, found
801.4721.
29: (77% yield, 73:27 dr) [t]D +19.2 (c 2.72, 21 oC, CHC13); IR 2958 (s), 2859 (s), 2252 (w),
1740 (w), 1472 (m), 1256 (s), 1107 (s), 909 (s); 1H NMR (500 MHz, CDCL3) 6 7.66 (m, 4H),
7.46 (m, 2H), 7.40 (m, 4H), 5.67 (nOe 7.4%) (d, J = 9.5 Hz, 1H), 4.56 (q, J - 7.0 Hz, 1H), 4.28
(nOe 7.4%, 4.4%) (dd, J = 6.5, 3.5 Hz, 1H), 4.12 (nOe 4.4%) (m, 1H), 3.83 (s, 1H), 2.71 (dd, J =
17.5, 6.0 Hz, 1H), 2.66 (m, 1H), 2.49 (dd, J = 17.5, 8.0 Hz, 1H), 1.86 (m, 2H), 1.56 (d, J = 1.0
Hz, 3H), 1.52 (d, J = 6.5 Hz, 3H), 1.07 (s, 9H), 1.00 (s, 9H), 0.99 (s, 3H), 0.93 (s, 9H), 0.91 (d, J
= 7.5 Hz, 3H), 0.84 (s, 3H), 0.21 (s, 3H), 0.20 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H); 13 C (125.8
MHz, CDC13) 6 171.2, 157.3, 135.9, 133.6, 133.4, 132.8, 130.3, 130.2, 128.9, 128.1, 128.0, 99.2,
82.8, 65.7, 46.4, 40.1, 37.3, 34.2, 27.0, 26.8, 26.8, 26.6, 26.4, 21.4, 21.2, 19.4, 19.2, 19.0, 12.0,
11.8, -2.4, -2.5, -2.9, -3.3; HRMS m/z (ESI, M+Na') calcd 801.4742, found 801.4735.
100
(+)-Non-l-en-4-ol (56):
OH
56
Copper (I) iodide (80 mg, 0.4 mmol) was placed in a round bottomed flask and cooled to -78
oC.
To this was added vinyl magnesium bromide generated from magnesium (540 mg, 22 mmol)
and an excess of vinyl bromide (1 M, THF). The vessel was warmed to -10 oC and (R)-1,2heptene-oxide (1.14 g, 10 mmol) in THF (3.0 mL) was added dropwise.
The reaction was
allowed to gradually warm to 0 oC over 1.5 hours and then carefully quenched via the addition of
saturated aqueous ammonium chloride. The solution was extracted with diethyl ether and the
combined organics were dried over magnesium sulfate, filtered, concentrated (0 'C, 40 mmHg),
and purified by silica gel chromatography (10:1 hexanes/diethyl ether) to give 980 mg (69%) of
56 as a clear oil. Spectral data matched that known in the literature. 3 [a]D +7.4 (c 0.9, 21 'C,
CHC13); 1H NMR (500 MHz, CDCl 3)6 5.84 (m, 1H), 5.15 (m, 2H), 3.66 (m, 1H), 2.32 (m, 1H),
2.14 (m, 1H), 1.40-1.26 (bm, 8 H), 0.90 (t, J = 7.0 Hz, 3H);
13C
(125.8 MHz, CDCI 3)6 135.1,
118.3, 70.9, 42.2, 37.0, 32.1, 25.6, 22.8, 14.3.
(-)-l-Triethylsiloxy-3-acetoxy octane (30):
OAc
n-Bu
30
OSiEt 3
To a cold (0 'C) solution of 56 (140 mg, 1.0 mmol) in CH 2C12 (3 mL) was added triethylamine
(420 [iL, 3.0 mmol), acetic anhydride (140 pL, 1.5 mmol) and DMAP (12 mg, 0.10 mmol), this
was warmed to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride
and diethyl ether were added and the phases separated, the aqueous phase was extracted with
diethyl ether and the combined organics washed with brine and dried over magnesium sulfate.
The residual solvent was removed (0 oC, 70 torr) and the residue purified by silica gel
chromatography (4:1 hexanes:diethyl ether) to give 183 mg (100%) of the acetate protected
alcohol a portion of which was used in the subsequent steps. Ozone was bubbled through a
solution of the acetate protected alcohol (60 mg, 0.33 mmol) in methanol (2 mL) at -78 oC until
101
the solution turned blue, at which point the ozone was removed by bubbling argon through the
solution until it was colorless. NaBH 4 (25 mg portions) was added until TLC determined that
the reactant had been fully reduced to the primary alcohol.
Saturated aqueous ammonium
chloride was added and the product extracted with ethyl acetate. The combined organic layers
were washed with brine, dried over magnesium sulfate and concentrated.
The residue was
dissolved in DMF (1 mL) and cooled to 0 oC, to this was added chlorotriethylsilane (83 gpL, 0.49
mmol) and imidazole (40 mg, 0.59 mmol) and the reaction was warmed to room temperature and
stirred for 2 hours. Water and ethyl acetate were added and the aqueous phase extracted with
ethyl acetate, the combined organics were washed with brine, dried over magnesium sulfate,
concentrated and purified by silica gel chromatography (10:1 hexanes:diethyl ether) to give 66
mg (68% over two steps) of 30 as a clear oil. [a]D -10.2 (c 1.43, 21 'C, CHCl 3); IR 2956 (s),
2876 (m), 1740 (s), 1375 (m), 1243 (s); 'H NMR (500 MHz, CDCl 3)6 4.97 (xq, J= 6.5 Hz, 1H),
3.64 (t, J= 7.0 Hz, 2H), 2.04 (s, 3H), 1.79 (q, J= 6.5 Hz, 2H), 1.56 (m, 2H), 1.30 (bin, 6H), 0.96
(t, J= 8.0 Hz, 9H), 0.88 (t, J= 6.5 Hz, 2H), 0.59 (q, J= 8.0 Hz, 6H); "3 C (125.8 MHz, CDC13) 3
170.9, 72.1, 59.6, 37.4, 34.5, 31.9, 25.0, 22.8, 21.5, 14.2, 7.0, 4.5; HRMS m/z (ESI, M+Na +)
calcd 325.2175, found 325.2154.
(+)-Alcohol (31):
OTBDPS
O
O
'"OTBS
n-Bu
TBSO
31
OH
ý'
,Me
n-BuLi (2.5 M in hexanes, 110 gL, 0.28 mmol) was added to a cold (-10 'C) solution of
iPr 2NH (38 tiL, 0.27 mmol) in THF (1.8 mL) the solution was stirred for 15 minutes, then cooled
to -78 'C. A solution of 30 (78 mg, 0.26 mmol) in THF (0.9 mL) was added dropwise and the
reaction stirred for 10 minutes at -78 'C and 3 minutes at -42 oC, a solution of 29 (80 mg, 0.10
mmol) in THF (1.8 mL) was added dropwise and the reaction stirred for 2 hours at -42 'C. The
reaction was quenched by the addition of water and the product extracted with diethyl ether, the
102
combined organics were washed with brine and dried over magnesium sulfate.
The crude
material was concentrated and passed through a plug of silica gel (load with hexanes flush with
30:1 hexanes:diethyl ether), the eluent was collected, concentrated and placed in a flask with
methanol (15 mL) along with citric acid (46 mg, 0.22 mmol). The suspension was heated to 65
oC
and stirred for 35 minutes (at which point the solution became homogeneous). The solvent
was removed in vacuo and the residue purified by chromatography (hexanes
-
7:1
hexanes:diethyl ether) to give 76 mg (75% over two steps) of 31 as a clear oil. [a]D +3.8 (c 1.0,
22 TC, CHC13); IR 3842 (bm), 3073 (w), 2957 (s), 2858 (s), 1733 (m), 1664 (m), 1473 (m), 1381
(m), 1318 (m), 1254 (s), 1112 (s), 1041 (s), 837 (s), 774 (s), 736 (s), 702 (s); 1H NMR (500
MHz, CDC13)6 7.66 (m, 4H), 7.38 (m, 6H), 5.58 (d, J = 9.5 Hz, 1H), 5.04 (m, 1H), 4.52 (q, J =
7.0 Hz, 1H), 4.14 (tt, J= 11.0, 4.5 Hz, 1H), 3.81 (s, 1H), 3.57 (m, 3H), 3.10 (s, 3H), 2.81 (d, J=
13.5 Hz, 1H), 2.60 (dd, J= 9.0, 7.5 Hz, 1H), 2.52 (d, J= 13.5 Hz, 1H), 2.45 (dd, J= 8.0, 5.0 Hz,
1H), 2.25 (dd, J= 13.0, 3.5 Hz, 1H), 1.85 (m, 1H), 1.64 (m, 4H), 1.53 (d, J= 7.0 Hz, 3H), 1.49
(s, 3H), 1.30 (bm, 6H), 1.05 (s, 9H), 1.01 (s, 9H), 1.00 (s, 3H), 0.92 (s, 9H), 0.89 (m, 6H), 0.84
(s, 3H), 0.21 (s, 3H), 0.20 (s, 3H), 0.10 (s, 3H), 0.06 (s, 3H);
13C
(125.8 MHz, CDC13) 6 170.5,
157.5, 136.0, 135.9, 134.8, 134.6, 130.9, 130.1, 129.7, 127.7, 127.7, 99.6, 99.0, 80.9, 74.4, 72.1,
66.9, 58.7, 47.8, 46.4, 43.1, 42.8, 38.7, 37.6, 34.7, 33.9, 31.8, 27.2, 26.8, 26.6, 25.3, 22.9, 22.7,
21.6, 19.4, 19.3, 14.4, 14.2, 12.8, 12.0, -2.4, -2.5, -2.9, -3.2; HRMS m/z (ESI, M+Na ) calcd
1003.6305, found 1003.6304.
Macrodiolide formation: 67
67
The material collected was a complex mixture of diastereomers, as would be expected for macrocyclicdimerization; therefore, full characterization was not performed and the assignment of these compounds is
tentative.
103
OTBDPS
32
1. Sml2,THF,
,\Me
1.NBS
2. Dess
O
"/OTBS
O
n-Bu
O
CHO
n-B
2. Martin
OeH
-Martin [O]
-78 OC
sulfurane
Br
DPS
Me
To a cooled (0 °C) solution of 31 (4 mg, 4 limole) in THF (0.3 mL) was added 50 RL of a
solution containing re-crystallized N-Bromosuccinimide (NBS) (14 mg, 0.081 mmol) in THF (1
mL), the reaction was stirred for 45 minutes then quenched with sodium bicarbonate.
The
solution was poured in to a mixture of brine and saturated aqueous sodium bicarbonate and the
product extracted with ethyl acetate. The combined organic layers were dried over magnesium
sulfate, filtered, concentrated and passed through a plug of silica (hexanes -- 20:1 hexanes/ethyl
acetate) to give the crude a-bromoketone, which was dissolved in CH 2C12 (200 1LL) and cooled to
0 'C. A stock solution of Dess-Martin periodinane (26 mg, 0.061 mmol) and pyridine (10 gtL,
0.1 mmol) in CH 2C1 2 (0.5 mL) was prepared, and a portion (100 [tL) was added to the solution of
the a-bromoketone.
The reaction was stirred for 80 minutes, concentrated and purified by
chromatography (15:1 hexanes:ethyl acetate), to give 32 as a clear oil (3.4 mg, 88% over two
steps). This material could not be stored, and was used immediately in the subsequent step.
SmI 2 (Strem, 0.1 M THF, 0.18 mL, 0.18 mmol) was added to a teardrop flask which had been
thoroughly purged with argon and cooled to -78 'C. A solution of 32 (3.4 mg, 3.6 i[mol) in
THF (0.9 mL) was added to the reaction vessel over 20 minutes and the reaction stirred for an
additional 75 min. Excess Sml2 was oxidized by bubbling dry air through the solution until the
solution turned yellow, the solution was poured into a separation funnel containing aqueous
sodium thiosulfate, sodium bicarbonate and diethyl ether, the layers were separated and the
aqueous layer extracted with diethyl ether. The combined organic layers were washed with
saturated aqueous sodium thiosulfate (2x), dried over magnesium sulfate, filtered, concentrated
and purified by chromatography: hexanes (flush out iodine) 4 10:1 hexanes/ethyl acetate to give
104
1.9 mg (61%) of what is presumed to be the macrodiolide as a mixture of diastereomers. 'H
NMR (integration values are based on the assumption of macrodiolide formation) (500 MHz,
CDCI 3) 6 7.65 (m, 8H), 7.39 (m, 12H), 5.60 (d, J= 9.0 Hz, 2H), 5.03 (m, 2H), 4.14 (m, 2H), 4.00
(s, 2H), 3.78 (m, 2H), 3.61 (m, 2H), 3.39 (s, 2H), 3.03 (s, 6H), 2.87 (m, 2H), 2.66 (d, J= 14.0
Hz, 2H), 2.56 (m, 1H), 2.50 (d, J= 14.0 Hz, 2H), 2.30 (m, 4H), 2.18 (s, 1H), 1.76 (m, 4H), 1.59
(m, 6H), 1.46 (m, 8H), 1.34-1.20 (m, 18H), 1.09 (m, 12H), 1.05 (s, 18 H), 0.94 (m, 12H), 0.90
(s, 18H), 0.14 (m, 4H), 0.80 (m, 4H), 0.02 (m, 4H), 0.02 (m, 4H); HRMS m/z (ESI, M+Na +)
calcd (desired macrocycle) = 887.5280, found 887.5284; calcd (macrodiolide) = 1753.0874,
found 1752.9927.
33:
To a cold (0 'C) solution of the macrodiolide (2 mg, 1 ptmol) in CH 2C1 2 (0.12 mL) was added
Martin sulfurane (Aldrich, 8 mg, 10 gpmol) and the reaction was stirred at 0 oC for 2 h, quenched
with saturated aqueous sodium bicarbonate and the product extracted with diethyl ether. The
combined organic layers were washed four times with 1 M NaOH and once with brine, dried
over magnesium sulfate, filtered, concentrated and purified by chromatography: hexanes 4 15:1
hexanes:diethyl ether to give <1 mg of 33. 'H NMR (500 MHz, CDC13) 6 7.65 (m, 8H), 7.40 (m,
4H), 7.36 (m, 8H), 5.89 (t, J
=
6.0 Hz, 1H), 5.57 (d, J= 9.0 Hz, 2H), 4.99 (m, 2H), 4.15 (m, 3H),
3.98 (s, 1H), 3.77 (m, 1H), 3.60 (d, J = 11.5 Hz, 2H), 3.40 (s, 1H), 3.03 (s, 3H), 3.02 (s, 3H),
2.88 (m, IH), 2.66 (d, J= 14.0 Hz, 1H), 2.61 (d, J = 14.0 Hz, 1H), 2.57 (m, 1H), 2.50 (d, J
=
14.0 Hz, 2H), 2.39 (m, 3H), 2.26 (m, 3H), 2.18 (s, 2H), 1.79 (s, 2H), 1.77 (m, 2H), 1.68-1.52 (m,
6H), 1.47 (m, 2H), 1.38-1.20 (m, 18H), 1.14 (s, 3H), 1.09 (m, 6H), 1.05 (s, 18H), 0.95 (m, 6H),
0.92 (m, 12H), 0.91 (s, 18H), 0.12 (m, 4H), 0.08 (m, 4H), 0.03 (m, 4H); HRMS m/z (ESI,
M+Na ) calcd 1734.0570, found 1734.0549.
(+)-4-Triethylsilyoxylnonene (57):
OSiEt 3
57
To a cold (0
oC)
solution of 56 (47 mg, 0.33 mmol) in DMF (1 mL) was added imidazole (110
mg, 1.6 mmol) and chlorotriethylsilane (220 .l, 1.3 mmol), the mixture was warmed to room
105
temperature and stirred for 4 h.
The reaction was quenched with water and extracted with
diethyl ether. The combined organic extracts were washed with brine, dried over magnesium
sulfate, filtered, concentrated (rt, 60 mmHg) and purified by chromatography (hexanes) to give
57 as a clear oil (68 mg, 80%). ["]D +11.4 (c 0.78, 22 oC, CHC13); IR 2956 (s), 2876 (s), 1458
(m), 1239 (m), 1005 (in), 911 (m), 724 (s); 1H NMR (500 MHz, CDC13) 6 5.83 (ddt, Jt = 7.0, Jd =
17.5, 10.0 Hz, 1H), 5.04 (m, 2H), 3.69 (quint, J = 6.0, 1H), 2.22 (m, 2H), 1.50-1.25 (bm, 8H),
0.97 (t, J = 7.5, 9H), 0.89 (t, J =7.0, 3H), 0.61 (q, J = 7.5, 6H);
13C
(125.8 MHz, CDCl 3) 3
135.6, 116.8, 72.3, 42.3, 37.1, 32.2, 25.3, 22.9, 14.3, 7.2, 5.2; HRMS m/z (ESI, M+Na +) calcd
279.2115, found 279.2106.
(-)-3-triethylsilyloxy octanal (24):
OSiEt 3
CHO
24
Ozone was bubbled through a cold (-78
oC)
solution of 57 (48 mg, 0.18 mmol) in CH 2C1 2 (4
mL) until a pale blue color was observed, the solution was degassed with argon, and
triphenylphosphine (-400 mg) in CH 2C12 (- 1 g/mL) was added. The solution was allowed to
warm to -15 'C over two hours, concentrated and purified by silica gel chromatography (50:1
hexanes/CH 2Cl 2 -- 5:1 hexanes/diethyl ether) to give 24 as a colorless oil (46 mg, 96%). [a]D
7.9 (c 0.43, 21 'C, CHC13); IR 2956 (s), 2877 (s), 1727 (s), 1457 (w), 1379 (w), 1240 (w), 1102
(m), 1005 (m); 'H NMR (500 MHz, CDC13) 6 9.82 (t, J
=
2.5 Hz, 1H), 4.20 (q, J = 6.0 Hz, 1H),
2.53 (m, 2H), 1.60-1.49 (bm, 2H), 1.37-1.25 (bm, 6H), 0.96 (t, J = 8.0 Hz, 9H), 0.90 (t, J = 7.0
Hz, 3H), 0.61 (q, J= 8.0 Hz, 6H);
13C
(125.8 MHz, CDC13)6 202.7, 68.4, 51.1, 38.2, 32.0, 25.1,
22.8, 14.2, 7.0, 5.2; HRMS m/z (ESI, M+Na +) calcd 281.1907, found 281.1898.
a-Bromo-ketone (36):
106
ES
To a cooled (0
oC)
solution of 23 (800 mg, 1.0 mmol) in THF (45 mL) was added re-
crystallized N-Bromosuccinimide (NBS) (200 mg, 1.1 mmol) and the reaction was stirred for 45
minutes then quenched with sodium bicarbonate. The solution was poured in to a mixture of
brine and saturated aqueous sodium bicarbonate and the product extracted with ethyl acetate.
The combined organic layers were dried over magnesium sulfate, filtered, concentrated and
purified by chromatography (hexanes - 10:1 hexanes/ethyl acetate 4- 6:1 hexanes/ethyl acetate)
to give 760 mg (100%) of 36 as a 3:1 mixture of diastereomers (spectral data for major
diastereomer only). IR 3473 (bw), 3072 (w), 2959 (s), 2877 (s), 1742 (s), 1711 (m), 1472 (m),
1428 (m), 1233 (s), 1113 (s), 1009 (s) 703 (s); 1H NMR (500 MHz, CDCl3) 5 7.65 (m, 4H), 7.46
(m, 2H), 7.40 (Vt, J = 7.0 Hz, 4H), 5.60 (d, J =9.5 Hz, 1H), 4.72 (q, J =6.5 Hz, 1H), 4.30 (dd, J
= 11.5, 3.0 Hz, 1H), 4.12 (m, 1H), 3.40 (d, J = 1.0 Hz, 1H), 2.71 (dd, J = 17.5, 6.0 Hz, 1H), 2.49
(dd, J = 17.5, 8.0 Hz, 1H), 2.38 (apparent quintet, J = 7.5 Hz, 1H), 1.90 (m, 1H), 1.83 (m, 1H),
1.68 (d, J = 6.5 Hz, 3H), 1.56 (s, 3H), 1.22 (s, 3H), 1.17 (s, 3H), 1.07 (s, 9H), 1.00 (m, 9H), 0.93
(d, J = 7.5 Hz, 3H), 0.68 (m, 6H);
13C
(125.8 MHz, CDC13) 6 209.5, 170.9, 135.8, 133.6, 133.3,
131.0, 130.4, 130.3, 130.2, 128.1, 128.0, 124.9, 82.2, 81.5, 65.6, 54.2, 41.4, 40.0, 37.3, 35.4,
27.0, 25.4, 21.3, 21.1, 19.2, 11.9, 7.4, 7.4, 5.8, 5.8; HRMS m/z (ESI, M+Na ÷) calcd 765.2977,
found 765.2975.
(+)-Enone (39):
107
OTBDPS
i0
H
TESO
n-Bu
n-Bu
..,\Me
"/OTES
0
Me
39
SmI 2 (Strem, 0.1 M THF, 50 mL, 5.0 mmol) was added to a 500 mL teardrop flask which had
been thoroughly purged with argon and cooled to -78 'C. A solution of 36 (765 mg, 1.03
mmol) and 24 (280 mg, 1.1 mmol) in THF (52 mL) was added to the reaction vessel over 15
minutes and the reaction stirred for an additional 70 minutes. Excess SmI2 was oxidized by
bubbling dry air through the solution until the solution turned yellow, the solution was poured
into a separation funnel containing aqueous sodium thiosulfate, sodium bicarbonate and diethyl
ether, the layers were separated and the aqueous layer extracted with diethyl ether.
The
combined organic layers were washed with saturated aqueous sodium thiosulfate (2x), dried over
magnesium sulfate, filtered, concentrated and purified by chromatography: hexanes (flush out
iodine) -
10:1 hexanes/ethyl acetate -> 6:1 hexanes/ethyl acetate to give 58 as a mixture of 4
diastereomers (850 mg, 90%). IR 3503 (bm), 2957 (s), 2876 (s), 1744 (s), 1700 (s), 1462 (s),
1379 (s), 1235 (s), 1112 (s), 1009 (s), 739 (s), 702 (s); HRMS m/z (ESI, M+Na +) calcd 945.5887,
found 945.5880. To a cold (0
oC)
solution of 58 (852 mg, 0.924 mmol) in CH 2C12 (70 mL) was
added Martin sulfurane (Aldrich, 4.3 g, 6.4 mmol) and the reaction was stirred at 0 oC for 2 h,
sealed and placed in a freezer (-4
oC)
for 50 h. The reaction was quenched with saturated
aqueous sodium bicarbonate and the product extracted with diethyl ether. The combined organic
layers were washed four times with 1 M NaOH and once with brine, dried over magnesium
sulfate, filtered, concentrated and purified by chromatography: hexanes ether (400 mL flush) 4
15:1 hexanes:diethyl
13:1 hexanes:ethyl acetate to give 660 mg (80%) 39 as a single
detectable isomer. [a]D +20.5 (c 1.28, 21 'C, CHC13); IR 2957 (s), 2933 (s), 2876 (s); 1746 (m),
1654 (w), 1463 (w), 1379 (w), 1231 (m), 1112 (s), 1008 (m), 739 (s); 'H NMR (500 MHz,
CDC13) 6 7.65 (m, 4H), 7.46 (m, 2H), 7.40 (Wt, J = 7.5 Hz, 4H), 6.05 (t, J = 9.5 Hz, 1H), 4.29
(dd, J = 7.0, 3.0 Hz, 1H), 4.18 (s, 1H), 4.11 (m, IH), 3.78 (q, J = 5.5 Hz, 1H), 2.71 (dd, J = 17.5,
6.0 Hz, 1H), 2.49 (dd, J = 17.5, 8.5 Hz, 1H), 2.38 (q, J = 8.0 Hz, 1H), 2.32 (t, J = 6.0 Hz, 2H),
108
1.91 (m, 1H), 1.83 (m, 1H), 1.78 (s, 3H), 1.56 (s, 3H), 1.42 (bm, 3H), 1.32-1.24 (bm, 6H), 1.17
(s, 3H), 1.07 (s, 9 H), 1.03 (s, 3H), 1.01-0.93 (bm, 20H), 0.88 (t, J = 7.0 Hz, 3H), 0.66 (q, J =
8.0 Hz, 6H), 0.60 (q, J = 8.0 Hz, 6H); 13C (125.8 MHz, CDCI 3) 6 211.2, 171.0, 138.0, 135.8,
133.6, 133.4, 132.1, 131.9, 130.8, 130.3, 130.2, 129.7, 128.1, 128.0, 82.3, 80.9, 71.6, 65.7, 54.2,
40.1, 37.3, 37.3, 36.5, 35.3, 32.2, 27.0, 25.5, 25.4, 22.9, 21.1, 20.8, 19.2, 14.8, 14.3, 12.0, 7.4,
7.1, 5.9, 5.2; HRMS m/z (ESI, M+Na +) calcd 927.5781, found 927.5770.
(-)-i-Hydroxy enone (59):
n-Bu
A solution of HF (49% aqueous, 800 [pL, 24.4 mmol) in MeCN (7.2 mL) was added to 39 (88
mg, 97 pmol) in a plastic vial.
After 4 minutes the vial was rinsed (diethyl ether) into a
separation funnel containing aqueous sodium bicarbonate. The two phases were separated and
the aqueous phase was extracted twice with ethyl acetate, the combined organic layers were
washed with sodium bicarbonate and brine, dried over sodium sulfate, filtered, concentrated and
purified by silica gel chromatography (8:1 hexanes:ethyl acetate 4 3:1 hexanes:ethyl acetate) to
give 59 as a clear oil (45 mg, 68%). [a]D -11.1 (c 0.33, 24 'C, CHCI3); IR 3446 (bm), 2958 (s),
2930 (s), 2858 (s), 1734 (s), 1653 (w), 1472 (m), 1428 (m), 1379 (m), 1240 (m), 1112 (s); 'H
NMR (500 MHz, CDC13) 6 7.64 (apparent dd, J = 8.0, 1.5 Hz, 4H), 7.47 (m, 2H), 7.41 (apparent
dt, Jt = 7.5, Jd = 1.5 Hz, 4H), 5.97 (dt, Jt = 7.0, Jd = 1.5 Hz, 1H), 5.44 (d, J = 10.5 Hz, 1H), 4.34
(dd, J = 12.0, 3.5 Hz, 1H), 4.11 (m, 1H), 3.85 (d, J = 7.5 Hz, 1H), 3.71 (m, 1H), 3.56 (dd, J =
7.5, 2.5 Hz, 1H), 2.67 (m, 2H), 2.47 (dd, J = 17.5, 8.0 Hz, 1H), 2.30 (m, 1H), 2.23 (m, 1H), 2.13
(d, J = 5.0 Hz, 1H), 1.90 (m, 1H), 1.84 (m, 1H), 1.78 (s, 3H), 1.62 (d, J = 1.0 Hz, 3H), 1.45 (m,
3H), 1.30 (bm, 8 H), 1.20 (s, 3H), 1.06 (s, 9H), 1.02 (d, J = 7.0 Hz, 3H), 0.89 (t, J = 7.0 Hz, 3H);
13
C (125.8 MHz, CDC13 ) 6 216.0, 171.2, 138.0, 135.8, 135.8, 133.5, 133.3, 132.3, 131.2, 131.2,
130.3, 130.3, 128.1, 128.1, 82.8, 77.4, 71.0, 65.5, 50.2, 40.0, 37.6, 37.4, 36.1, 34.4, 32.1, 27.0,
109
25.9, 25.6, 22.8, 22.8, 19.9, 19.2, 15.0, 14.3, 11.3; HRMS m/z (ESI, M+Na +) calcd 699.4051,
found 699.4055.
(-)-Triol (40):
n-Bu
To a cold (-10
oC)
solution of 59 (140 mg, 0.21 mmol) in THF (14 mL) was added
catecholborane (440 p.L, 4.1 mmol) and the reaction was stirred at -10 oC for 6 h. Methanol (4
mL) was carefully added to the reaction, followed by saturated aqueous potassium sodium
tartrate (4 mL), and pinacol (300 mg). The reaction was warmed to room temperature and stirred
overnight. The solution was diluted with ethyl acetate and then washed with 0.5 M NaOH until
the aqueous layer was colorless and then once with brine. The organic layer was dried over
sodium sulfate, filtered, concentrated and purified by chromatography (4:1 hexanes/ethyl acetate
-4 1:1 hexanes/ethyl acetate) to give 120 mg (87%) of 40 as a clear oil. Stereochemistry of the
diol, and olefin geometry was confirmed by nOe analysis of the acetonide (41). 40 (3.1 mg, 4.6
pmole) was reacted with 2,2-dimethoxypropane (2 eq) in acetone (0.01 M) and catalytic CSA
(0.2 eq) to give 41 (3.1 mg, 95%) after chromatography (hexanes 4 3:1 hexane/ethyl acetate).
40: [a]D -4.8 (c 0.18, 22 'C, CHCI3); IR 3386 (bm), 2958 (s), 2930 (s), 2858 (s), 1734 (s), 1428
(s), 1379 (s), 1260 (m), 1112 (s), 1011 (s), 823 (w); 'H NMR (500 MHz, CDCl 3) 6 7.65
(apparent dd, J = 8.0, 1.5 Hz, 4H); 7.46 (m, 2H), 7.40 (m, 4H), 5.70 (d, J = 10.0 Hz, 1H), 5.47
(t, J = 7.5 Hz, 1H), 4.38 (dd, J = 12.0, 3.0 Hz, 1H), 4.12 (m, 1H), 3.98 (s, 1H), 3.67 (bs, 1H),
3.55 (s, 1H), 3.52 (bs, 1H), 2.68 (m, 2H), 2.48 (dd, J = 17.0, 8.5 Hz, 1H), 2.22 (t, J = 7.0 Hz,
2H), 1.94 (dt, Jt = 3.5, Jd = 13.0 Hz, 1H), 1.87 (m, 1H), 1.68 (s, 3H), 1.64 (d, J = 1.0 Hz, 3H),
1.49-1.44 (bm, 3H), 1.36-1.26 (bm, 6H), 1.07 (s, 9H), 1.03 (d, J = 7.0 Hz, 3H), 0.90 (t, J = 7.0
Hz, 3H), 0.88 (s, 3H), 0.71 (s, 3H);
13C
(125.8 MHz, CDC13) 6 171.1, 138.5, 135.9, 135.8, 133.6,
133.4, 131.5, 130.3, 130.2, 130.0, 128.1, 128.0, 126.0, 87.3, 83.8, 82.6, 71.9, 65.7, 42.6, 40.1,
110
37.4, 37.4, 35.9, 34.1, 32.1, 27.0, 25.6, 22.8, 20.3, 19.2, 15.9, 15.3, 14.3, 11.5; HRMS m/z (ESI,
M+Na +) calcd 701.4208, found 701.4212.
41: [a]D -16.5 (c 0.5, 24 oC, CHCl3); IR 3447 (bm), 2959 (s), 2931(s), 2859 (s), 1741 (s), 1465
(m), 1428 (m), 1378 (s), 1254 (s), 1168 (m), 1112 (s), 702 (s); 'H NMR (500 MHz, CDC13) 6
7.65 (m, 4H), 7.46 (apparent t, J = 7.0 Hz, 2H), 7.40 (m, 4H), 5.71 (d, J = 9.5 Hz, 1H), 5.38
(nOe 7.1%) (t, J = 7.0 Hz, 1H), 4.37 (dd, J = 12.5, 3.0 Hz, 1H), 4.12 (m, 1H), 3.91 (nOe 7.1%,
5.0%) (s, 1H), 3.66 (m, 1H), 3.43 (nOe 5.0%) (s, 1H), 2.68 (m, 2H), 2.49 (dd, J = 17.0, 8.0 Hz,
1H), 2.23 (m, 2H), 1.94 (dt, Jt = 3.5, Jd = 13.0 Hz, 1H), 1.86 (m, 1H), 1.66 (s, 3H), 1.63 (d, J =
1.0 Hz, 3H), 1.46 (m, 3H), 1.44 (s, 3H), 1.43 (s, 3H), 1.32-1.26 (m, 6H), 1.07 (s, 9H), 0.97 (d, J
= 7.0 Hz, 3H), 0.90 (t, J = 7.0 Hz, 3H), 0.76 (s, 3H), 0.74 (s, 3H);
13C
(125.8 MHz, CDC13) 6
171.2, 135.9, 135.8, 135.4, 133.6, 133.4, 132.7, 130.3, 130.2, 129.1, 128.1, 128.0, 126.0, 98.8,
84.3, 82.6, 82.0, 71.9, 65.7, 40.1, 38.3, 37.3, 37.2, 36.2, 32.1, 31.8, 31.8, 30.2, 27.0, 25.6, 22.8,
22.2, 20.7, 19.4, 19.2, 15.6, 15.3, 14.3, 11.6; HRMS m/z (ESI, M+Na +) calcd 741.4521, found
741.4504.
Seco Acid (42):
OTBDPS
n-
42
Me
n-BuLi (2.5 M in hexanes, 359 ptL, 0.90 mmol) was added to a cold (-10 oC) solution of
iPr 2NH (130 pL,0.90 mmol) in THF (8 mL) the solution was stirred for 15 minutes, then cooled
to -78 oC. A solution of ethyl acetate (88 piL, 0.90 mmol) in THF (3 mL) was added dropwise
and the reaction stirred for 5 minutes at -78 TC. 40 (61 mg, 0.090 mmol) was added as a solution
in THF (5 mL + 3 mL rinse) over 2 minutes and the reaction was warmed to -42 oC and stirred
for 1 hour. 0.1 M NaHSO 4 was added to stop the reaction and the product was extracted with
ethyl acetate, the combined organics were washed with brine, dried over sodium sulfate, and
concentrated to leave a pale yellow oil. The residue was dissolved in methanol (28 mL), placed
111
in a sealed tube along with 60 mg (0.28 mmol) of citric acid and heated to 70 oC for 2 hours.
The reaction was cooled to room temperature, diluted with ethyl acetate, washed with sodium
bicarbonate and brine, dried over sodium sulfate, and concentrated. Upon TLC examination two
spots were observable, the major was ethyl acetate (and methanol) addition to lactone, and the
minor was the same but with an acetate protection at C 17. Both spots were isolated by silica gel
chromatography (4:1 hexanes:ethyl acetate -- 1:1 hexanes:ethyl acetate) and then recombined.
The combined products were dissolved in water/methanol/THF (1.55 mL, 3.1 mL, 3.1 mL) and
LiOH (65 mg, 1.55 mmol) was added and the solution stirred overnight. Ethyl acetate was added
and two phases were separated. The organic phase was washed with saturated aqueous sodium
bicarbonate and brine then dried over sodium sulfate and concentrated. This gave 42 (43 mg,
64% over 3 steps) in >90% purity (by 'H NMR). 'H NMR (500 MHz, CDC13) 6 7.66 (m, 4H),
7.43 (m, 2H), 7.38 (m, 4H), 5.66 (d, J= 9.0 Hz, 1H), 5.48 (t, J= 7.0 Hz, 1H), 4.13 (m, 1H), 3.99
(s, 1H), 3.85 (d, J= 11.5 Hz, 1H), 3.67 (m, 1H), 3.53 (s, 1H), 2.79 (d, J= 15.0 Hz, 1H), 2.69 (m,
1H), 2.52 (d, J= 15.0 Hz, 1H), 2.24-2.17 (m, 3H), 2.08-2.02 (m, 2H), 1.70-1.68 (m, 2H), 1.68
(s, 3H), 1.64 (m, 1H), 1.58 (s, 3H), 1.50-1.42 (m, 4H), 1.34-1.24 (m, 8H), 1.05 (s, 9H), 1.02 (d,
J= 7.0 Hz, 3H), 0.90 (t, J= 6.5 Hz, 3H), 0.88 (s, 3H), 0.72 (s, 3H); HRMS m/z (ESI, M+Na +)
calcd 775.4578, found 775.4606.
Ene-ester (44):
OTBDPS
0~0,,,Me
H
0
0
'"OH
n-Bu••
OH
44
Me
Typically reactions were run on a 28 mg scale andgave 5-11 mg (20-42%) of the products.
42 (6.4 mg, 8.5 iimole) was loaded into a 10 mL round-bottomed flask and azeotroped twice
with anhydrous toluene. A stock solution was prepared by dissolving triethylamine (46 [tL, 0.33
mmol) and 2,4,6-trichlorobenzoyl chloride (46 gL, 0.30 mmol) in THF (8.3 mL). A portion (714
ptL) of the stock solution was added to the flask containing 42. The solution was stirred at room
112
temperature for 15 hours -if after that time the solution was 'cloudy' the yields were generally
low, if the solution was clear with a noticeable amount of white precipitate the yields were
generally higher- then filtered through a cotton stuffed pipette and concentrated. The product
azeotroped twice with anhydrous toluene. The yellow residue was then dissolved in anhydrous
toluene (3 mL) and added over 7 hours via syringe pump to a solution of refluxing DMAP (6.2
mg, 0.051 mmol) in toluene (8.4 mL). After addition was complete the suspension was stirred
for an additional 30 minutes and then cooled to room temperature, diluted with ethyl acetate,
washed with 0.1 M NaHSO 4 and brine, dried over magnesium sulfate, filtered and concentrated.
Purification by silica gel chromatography (hexanes -
10:1 hexanes:ethyl acetate--6:1
hexanes:ethyl acetate) provided a mixture of 44 and 43 (4.2 mg total, 82:18 44:43, 70%). 'H
NMR (500 MHz, CDCl 3) 6 7.67 (m, 2H), 7.43 (m, 2H), 7.38 (m, 4H), 5.53 (d, J= 10.0 Hz, 1H),
5.25 (dd, J= 8.5, 4.0 Hz, 1H), 4.82 (m, 1H), 4.64 (s, 1H), 4.59 (t, J= 8.5 Hz, 1H), 4.15 (d, J=
11.5 Hz, 1H), 3.95 (s, 1H), 3.48 (s, 1H), 3.13 (d, J = 15.0 Hz, 1H), 2.91 (s, 1H), 2.87 (m, 1H),
2.31 (m, 1H), 2.11 (m, 1H), 1.94 (m, 1H), 1.80 (dd, J= 13.0, 7.0 Hz, 1H), 1.71 (s, IH), 1.65 (s,
3H), 1.64 (d, J = 1.5 Hz, 3H), 1.64 (d, J = 1.5 Hz, 3H), 1.50-1.40 (m, 2H), 1.32-1.22 (m, 6H),
1.07 (s, 9H), 1.00(t, J= 7.0 Hz, 3H), 1.00 (s, 3H), 0.87 (t, J= 7.0 Hz, 3H), 0.72 (s, 3H). HRMS
m/z (ESI, M+Na +) calcd 725.4208, found 725.4227.
(-)-Alkoxyacetylene tetraol (47):
n-BuLi (2.5 M in hexanes, 120 gL, 0.29 mmol) was added dropwise to a cold (-10 oC)
solution of iPr 2NH (40 gL, 0.29 mmol) in THF (7.2 mL) and the solution stirred for 15 minutes
113
Ethoxyethyne (63 wt% in hexanes, 45 ý1 L, 0.29 mmol)6 8 was
then cooled to -78 oC.
subsequently added, and the solution stirred for 50 minutes.
After dry (azeotroped with
anhydrous toluene) 40 (20 mg, 0.029 mmol) in THF (500 [tL) was added dropwise down the side
of the reaction vessel the reaction was stirred for 10 minutes at -78 'C and then warmed to -42
'C for 45 minutes. The reaction was quenched with pH 7.2 phosphate buffer and diluted with
diethyl ether. The aqueous phase was extracted twice with ethyl acetate and the combined
organic layers were washed with sodium bicarbonate and brine, and dried over sodium sulfate.
The slurry was filtered, concentrated, and purified by chromatography (3:2 hexanes:ethyl acetate
-- 4:5 hexanes:ethyl acetate) to give 47 as a clear oil (16 mg, 72%). Stereochemistry is
unassigned, dr >10:1. [a]D -16.1 (c 0.4, 21 oC, CHC13); IR 3365 (bm), 2929 (s), 2857 (s), 2226
(s), 1717 (w), 1654 (m), 1471 (m), 1428 (m), 1111 (s), 1008 (s), 703 (s); 'H NMR (500 MHz,
CDC13) 6 7.72 (m, 4H), 7.45 (m, 2H), 7.40 (m, 4H), 5.50 (d, J = 10.5 Hz, 1H), 5.46 (t, J = 7.0
Hz, 1H), 4.46 (apparent quint, J = 5.5 Hz, 1H), 4.25 (q, J = 7.0, 2H), 4.16 (d, J = 9.0 Hz, 1H),
3.99 (s, 1H), 3.66 (m, 1H), 3.50 (d, J = 2.0 Hz, 1H), 3.01 (bs, 1H), 2.82 (dd, J = 15.0, 7.5 Hz,
1H), 2.72 (dd, J = 15.0, 6.0 Hz, 1H), 2.65 (m, 1H), 2.48 (d, J = 2.5 Hz, 1H), 2.23 (t, J = 7.0 Hz,
2H), 1.75 (m, 1H), 1.69 (s, 3H), 1.50-1.40 (bm, 8H), 1.35-1.25 (bm, 9H), 1.06 (s, 9H), 0.98 (d, J
= 7.0 Hz, 3H), 0.92 (s, 3H), 0.90 (t, J = 7.0 Hz, 3H), 0.72 (s, 3H);
13C
(125.8 MHz, CDC13)
6
185.4, 138.7, 136.2, 136.2, 135.6, 133.5, 133.4, 130.1, 130.1, 127.9, 127.9, 127.0, 125.7, 103.6,
86.9, 84.3, 77.6, 74.0, 71.9, 69.2, 52.2, 45.3, 42.7, 41.3, 37.3, 36.0, 34.1, 32.1, 29.9, 27.1, 25.6,
22.9, 20.6, 19.5, 15.9, 15.2, 14.6, 14.3, 11.9; HRMS m/z (ESI, M+Na +) calcd 771.4627, found
771.4639.
(-)-Macrocycle, hemi-ketal (45):
OTBDPS
·\\Me
-
O
O HH
0
45
68
"'OH
Me
Although not utilized here, lithiated ethoxyethyne can be generated in situ and added directly to aldehydes and
114
Dry (azeotroped with anhydrous toluene) 47 (13 mg, 17 ptmol) in dry xylenes (24 mL) was
added dropwise over 5 hours to refluxing (150
oC)
xylenes (48 mL) and tri-n-butylamine (48 ýpL,
0.20 mmol). The reaction was stirred for an additional 20 minutes after the slow addition was
complete, then poured into a separation funnel containing ice, and diluted with ethyl acetate.
The organic layer was washed with 0.1 M NaHSO 4 and brine, dried over magnesium sulfate,
filtered, concentrated and purified by silica gel chromatography (20:1 hexanes:ethyl acetate 4
4:1 hexanes:ethyl acetate) to give 11 mg (90%) of 45 as a single diastereomer. [u]D -8.1 (c 0.19,
21 'C, CHC13); IR 3452 (bm), 2929 (s), 2858 (s), 1710 (m), 1428 (m), 1378 (m), 1208 (s), 1112
(s), 1058 (s), 998 (s), 702 (s); 'H NMR (500 MHz, CDC13) 5 7.67 (m, 4H), 7.43 (m, 2H), 7.38
(apparent t, J = 7.5 Hz, 4H), 5.42 (d, J = 10.5 Hz, 1H), 5.17 (d, J = 10.0 Hz, 1H) 5.12 (d, J = 2.0
Hz, 1H), 4.92 (m, 1H), 4.29 (apparent sept, J = 5.0 Hz, 1H), 4.12 (dd, J = 12.0, 2.0 Hz, 1H),
3.92 (s, 1H), 3.56 (s, 1H), 2.88 (m, 1H), 2.55 (d, J = 14.0 Hz, 1H), 2.47 (d, J = 14.0 Hz, 1H),
2.37 (m, IH), 2.04 (d, J = 14.0 Hz, 1H), 1.99 (dd, J = 12.0, 3.5 Hz, 1H), 1.71 (m, 1H), 1.66 (s,
3H), 1.62 (d, J = 1.0 Hz, 3H), 1.55-1.48 (bm, 2H), 1.40-1.32 (bm, 2H), 1.30-1.23 (bm, 8H),
1.06 (s, 9H), 1.01 (d, J = 7.0 Hz, 3H), 0.99 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.64 (s, 3H);
(125.8 MHz, CDC13)
6
3C
172.4, 136.3, 135.9, 134.5, 131.9, 131.4, 129.8, 129.8, 127.8, 127.8, 96.6,
81.2, 79.8, 76.5, 74.4, 66.5, 44.8, 44.2, 43.3, 38.6, 35.8, 34.1, 32.8, 31.8, 27.2, 25.1, 22.7, 22.2,
19.4, 19.4, 18.8, 14.2, 13.0, 11.1; HRMS m/z (ESI, M+Na +) calcd 743.4314, found 743.4334.
(+)-Macrocycle, methyl-ketal (43):
45 (11 mg, 16 jtmol), citric acid (3.8 mg, 19.8 gpmol) and methanol (30 mL) were combined in
a sealed tube and then heated to 75 oC overnight. The crude mixture was concentrated and
ketones: Raucher, S.; Bray, B. L. .1.Org. Chem. 1987, 52, 2332-2333.
115
purified by chromatography (20:1 hexanes:ethyl acetate 4 4:1 hexanes:ethyl acetate) to give 12
mg (100%) of 43. [a]D +15.2 (c 0.083, 22 'C, CHCl 3); IR 3447 (bm), 2926 (s), 2855 (s), 1725
(m), 1462 (m), 1378 (m), 1201 (m), 1113 (s), 1063 (s), 702 (s); 'H NMR (500 MHz, CDC13) 5
7.67 (d, J = 7.0 Hz, 4H), 7.44 (m, 2H), 7.38 (m, 4H), 5.63 (t, J = 7.0 Hz, 1H), 5.50 (d, J = 10.5
Hz, 1H), 4.78 (m, 1H), 4.17 (s, 1H), 4.12 (m, 1H), 3.76 (d, J = 11.5 Hz, 1H), 3.41 (d, J = 6.5 Hz,
1H), 2.98 (s, 3H), 2.86 (m, 1H), 2.74 (d, J = 13.5 Hz, 1H), 2.46 (d, J = 13.5 Hz, 1H), 2.44 (m,
IH), 2.20 (m, 1H), 2.01 (dd, J = 7.5, 4.5 Hz, 1H), 1.77 (m, 1H), 1.71 (s, 3H), 1.66 (m, 3H), 1.49
(bm, 2H), 1.37 (q, J = 11.5 Hz, 1H), 1.32-1.20 (bm, 9H), 1.05 (s, 9H), 1.01 (d, J = 7.0 Hz, 3H),
0.99 (s, 3H), 0.89 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H); 13 C (125.8 MHz, CDCl 3) 6 169.7, 136.4,
136.4, 135.1, 135.0, 132.1, 130.4, 130.3, 128.5, 128.3, 128.3, 126.4, 100.4, 83.4, 80.4, 77.9, 75.3,
75.1, 67.1, 49.6, 44.5, 44.3, 43.7, 39.1, 35.0, 34.4, 32.4, 31.9, 30.4, 27.6, 25.8, 24.6, 23.2, 21.9,
20.7, 19.8, 14.8, 14.7, 13.5, 13.4; HRMS m/z (ESI, M+Na +) calcd 757.4470, found 757.4464.
(+)-TES Ether (60):
OTBDPS
0
n-Bu
o
,\Me
0O
"OH
.,,'OTES
Me
60
43 (6.0 mg, 8.2 jimol) was loaded into a 5 mL RBF and azeotroped with anhydrous toluene,
placed under argon and cooled to -78 'C. Portions (200 gL) of a cold (0 oC) stock solution of
triethylsilyltriflate (TESOTf) (70 [tL, 0.31 mmol), 2,6-lutidine (71 [tL, 0.61 mmol) in CH 2 C12
(6.0 mL) were added, and the reaction progress checked by TLC (6:1 hexanes:ethyl acetate).
Additional portions of the stock solution were added until TLC indicated that all the 43 was
consumed. The reaction was quenched with methanol (70 p.L) diluted with diethyl ether and
washed with 0.1 M NaHSO 4 and brine, dried over magnesium sulfate, filtered, concentrated and
purified by chromatography (hexanes -
13:1 hexanes:ethyl acetate) to give 60 as a clear oil (5.8
mg, 83%). [a]D +34.9 (c 0.25, 22 'C, CHCl 3); IR 3546 (bw), 2955 (s), 2930 (s), 2875 (s), 1728
(s), 1458 (m), 1379 (m), 1238 (m), 1112 (s), 1066 (s), 1045 (s), 1008 (s), 702 (s); 1H NMR (500
116
MHz, CDC13) 6 7.68 (dd, J = 8.0, 1.5 Hz, 2H), 7.65 (dd, J = 8.0, 1.5 Hz, 2H), 7.44 (m, 2H), 7.38
(m, 4H), 5.80 (bs, 1H), 5.60 (d, J = 11.0 Hz, 1H), 4.88 (m, 1H), 4.20 (s, 1H), 4.14 (m, 1H), 3.64
(d, J = 12.0 Hz, 1H), 3.28 (d, J = 11.0 Hz, 1H), 2.96 (s, 3H), 2.92 (d, J = 14.5 Hz, 1H), 2.85 (m,
1H), 2.44 (m, 1H), 2.41 (d, J = 14.5 Hz, 1H), 1.97 (m, 2H), 1.90 (m, 1H), 1.72-1.67 (bm, 1H),
1.70 (s, 3H), 1.52 (s, 3H), 1.48-1.42 (bm, 1H), 1.34-1.24 (bm, 10H), 1.05 (s, 9H), 1.02 (bs, 2H),
0.98 (d, J = 6.5 Hz, 3H), 0.92 (t, J = 8.0 Hz, 9H), 0.92 (d, J = 5.0 Hz, 3H), 0.88 (t, J = 6.5 Hz,
3H), 0.54 (q, J = 8.0 Hz, 6H);
13
C (125.8 MHz, CDC13) 6 169.4, 136.0, 135.9, 134.6, 134.5,
131.0, 129.8, 127.8, 124.1, 99.6, 84.9, 79.8, 74.6, 73.0, 66.8, 48.1, 45.3, 43.4, 42.6, 39.0, 33.9,
33.5, 32.0, 31.1, 29.9, 27.1, 25.7, 22.8, 21.5, 19.2, 14.3, 14.1, 13.8, 7.3, 5.2; HRMS m/z (ESI,
M+Na +) calcd 871.5335, found 871.5358.
(+)-Ketone (61):
n-B
A portion (3.4 mL) of a stock solution of Dess-Martin periodinane (100 mg, 0.23 mmol) and
pyridine (93 pLL, 1.2 mmol) in CH 2C1 2 (7.1 mL) was added to 60 (5.6 mg, 6.6 ýtmol) and the
solution was stirred for 20 minutes. The solvent was removed in vacu. and the crude material
was purified by silica gel chromatography (hexanes -
11:1 hexanes/ethyl acetate) to give 26 as
a clear oil (5.5 mg, 98%). [a]D +116.8 (c 0.17, 22 'C, CHC13); IR 3361 (bw), 2926 (s), 2856 (s),
1726 (m), 1709 (w), 1380 (m), 1238 (w), 1111 (s), 1072 (s), 1046 (s), 702 (s); 'H NMR (500
MHz, CDC13) 6 7.68 (apparent dd, J = 8.0, 1.5 Hz, 2H), 7.65 (dd, J = 8.0, 1.5 Hz, 2H), 7.44 (m,
2H), 7.38 (m, 4H), 5.40 (d, J = 10.3 Hz, 1H), 5.25 (t, J = 6.6 Hz, 1H), 4.89 (m, 1H), 4.18 (s,
IH), 4.10 (m, 1H), 3.97 (m, 1H), 3.68 (d, J = 11.7 Hz, 1H), 2.94 (s, 3H), 2.88 (d, J = 14.3 Hz,
1H), 2.38 (d, J = 14.3 Hz, 1H), 2.27 (m, 2H), 1.97 (ddd, J = 12.8, 4.8, 1.6 Hz, 1H), 1.86 (dt, Jt =
2.2, Jd = 12.2 Hz, 1H), 1.78 (dd, J =12.7, 10.7 Hz, 1H), 1.67-1.61 (bm, 1H), 1.59 (s, 3H), 1.56
(s, 3H), 1.43-1.33 (bm, 1H), 1.32-1.22 (bm, 6H), 1.29 (s, 3H), 1.17 (q, J = 11.9 Hz, 1H), 1.05
117
(s, 9H), 1.01 (d, J = 6.6 Hz, 3H), 1.00 (s, 3H), 0.97 (t, J = 7.8 Hz, 9H), 0.87 (t, J = 7.0 Hz, 3H),
0.60 (q, J = 8.0 Hz, 6H); 13C (125.8 MHz, CDCl 3)6 214,8, 169.6, 137.8, 136.0, 135.9, 134.6,
134.4, 133.9, 129.9, 127.8, 125.3, 123.3, 99.5, 80.2, 74.6, 72.5, 66.6, 56.4, 48.4, 43.6, 42.0, 40.6,
38.9, 33.3, 32.1, 30.8, 27.1, 25.7, 24.4, 22.8, 19.4, 19.2, 18.8, 14.3, 13.8, 13.3, 7.3, 5.0; HRMS
m/z (ESI, M+Na +) calcd 869.5178, found 869.5146.
(+)-(5)-tert-Butyldiphenylsilanyloxy acutiphycin (16):
OTBDPS
le
n-B
61 (8.3 mg, 9.8 p~mol) was treated with 49% aqueous HF (74 ptL, 2.3 mmol) in MeCN (667
RL) at room temperature. After 3 minutes the reaction was poured into a separation funnel
containing aqueous sodium bicarbonate and diluted with diethyl ether. The organic layer was
washed with sodium bicarbonate and brine, dried over magnesium sulfate, filtered, concentrated,
and purified by silica gel chromatography (2:1 hexanes:diethyl ether) to give 49 as a white solid
(6.1 mg, 87%). The solid was crystallized using slow vapor diffusion of pentanes into diethyl
ether. mp 154-155 'C; la]D +131.2 (c 0.155, 22 'C, CHC13); IR 3428 (bs), 2957 (s), 2929 (s),
1703 (s), 1428 (m), 1379 (s), 1210 (m), 1112 (s). 'H NMR (500 MHz, CDC13)6 7.67 (apparent
d, J = 6.5 Hz, 4H), 7.43 (m, 2H), 7.38 (m, 4H), 5.25 (d, J = 9.8 Hz, 1H), 5.18 (dd, J = 11.1, 1.1
Hz, 1H), 5.15 (d, J = 2.6 Hz, 1H), 4.94 (m, 1H), 4.61 (d, J = 4.2 Hz, 1H), 4.28 (m, 1H), 4.12 (dd,
J = 11.7, 2.2 Hz, 1H), 3.90 (m, 1H), 2.59 (d, J = 14.6 Hz, 1H), 2.50 (d, J
=
14.6 Hz, 1H), 2.39
(ddd, J = 15.2, 10.7, 2.1 Hz, 1H), 2.08 (t, J = 13.5 Hz, 1H), 1.99 (dd, J = 12.2, 4.5 Hz, 1H), 1.75
(d, J = 1.1 Hz, 3H), 1.73-1.69 (m, 1H), 1.64 (s, 3H), 1.57-1.48 (m, 3H), 1.37 (dt, Jd = 2.4, Jt =
11.5 Hz, 1H), 1.32-1.22 (m, 7H), 1.09 (s, 3H), 1.07 (s, 9H), 1.02 (d, J = 6.4 Hz, 3H), 0.87 (t, J =
6.9 Hz, 3H), 0.83 (s, 3H);
3C
(125.8 MHz, CDC13)6 215.7, 172.6, 135.9, 135.3, 134.9, 134.4,
134.4, 130.7, 129.9, 129.9, 127.8, 126.6, 96.8, 79.9, 75.9, 74.2, 66.3, 52.8, 44.8, 44.2, 43.3, 38.5,
118
35.5, 32.9, 31.8, 27.2, 25.8, 25.2, 22.7, 19.4, 19.3, 16.2, 14.2, 13.1, 11.3; HRMS m/z (ESI,
M+Na +) calcd 741.4157, found 741.4150.
(+)-Acutiphycin (1):
OH
le
n-B
Me
Me
49 (3.9 mg, 5.4 itmol) was dissolved in THF (2.1 mL) and treated with 980 [IL of
TBAF/HOAc solution (TBAF 1 M THF, 2.5 mL; acetic acid 0.15 mL). The reaction was stirred
at room temperature for 52 hours, diluted with ethyl acetate and washed with sodium bicarbonate
(2x) and brine, dried over magnesium sulfate, filtered, concentrated and purified by silica gel
chromatography (3:2 diethyl ether:hexanes) to give 1 as a white solid (2.4 mg, 92%). mp 150151 'C; [a]D +151.6 (c 0.095, 21 'C, CH 2C12); IR (solution in CDC13) 3608 (m), 3457 (bw), 2985
(s), 2932 (m), 2902 (s), 1702 (m), 1643 (m), 1562 (m), 1298 (m), 1261 (m), 1216 (s), 1167 (s);
'H NMR (500 MHz, CDC13) 6 5.39 (d, J =2.4 Hz, 1H), 5.29 (m, 2H), 4.98 (m, 1H), 4.64 (d, J =
3.8 Hz, 1H), 4.33 (dd, J = 12.0, 2.1 Hz, 1H), 4.28 (m, IH), 4.95 (m, 1H), 2.67 (d, J =14.6 Hz,
1H), 2.62 (d, J = 14.6 Hz, 1H), 2.42 (ddd, J = 15.1, 10.7, 1.9 Hz, 1H), 2.18 (ddd, J = 11.9, 4.6,
1.3 Hz, 1H), 2.10 (apparent t, J = 13.6 Hz, 1H), 1.89 (dt, Jd = 12.2, Jt = 2.2 Hz, 1H), 1.78 (d, J =
1.3 Hz, 3H), 1.67 (s, 3H), 1.61-1.51 (m, 3H), 1.33-1.24 (m, 9H), 1.12 (s, 3H), 1.05 (d, J = 6.6
Hz, 3H), 0.89 (s, 3H), 0.88 (t, J = 6.9 Hz, 3H); 1H NMR (500 MHz, 1:1 C6D 6 :CDC13) 6 5.37 (bs,
1H), 5.21 (d, J = 10.4 Hz, 1HO, 5.16 (d, J = 11.2 Hz, 1H), 4.91 (m, 1H), 4.52 (s, 1H), 4.18 (d, J
= 11.9 Hz, 1H), 4.01 (tt, J = 11.1, 4.3 Hz, 1H), 3.87 (m, 1H), 2.42 (d, J = 14.4 Hz, 1H), 2.29 (d,
J = 14.4 Hz, 1H), 2.20 (ddd, J = 14.9, 10.7, 1.8 Hz, 1H), 1.97 (d, J = 12.8 Hz, 1H), 1.91 (m,
1H), 1.63 (s, 3H), 1.54 (m, 1H), 1.44 (s, 3H), 1.30 (m, 1H), 1.22-1.10 (m, 11H), 1.04 (m, 3H),
1.00 (dt, Jd = 2.2, Jt = 11.5 Hz, 1H), 0.85 (s, 3H), 0.82 (m, 3H); 13C (125.8 MHz, CDC13) 6 215.7,
172.6, 135.1, 135.0, 131.1, 126.6, 96.8, 79.9, 76.1, 74.4, 64.7, 52.8, 44.8, 43.9, 43.3, 38.2, 35.5,
32.9, 31.8, 25.8, 25.2, 22.7, 19.3, 16.3, 14.2, 13.1, 11.3; 13 C (125.8 MHz, DMSO-d6 ) 6 214.5,
119
170.9, 136.2, 134.9, 128.0, 123.6, 96.2, 77.3, 74.1, 73.8, 62.7, 53.1, 45.9, 43.5, 41.3, 38.2, 34.4,
31.7, 31.0, 24.4, 23.3, 22.0, 20.7, 16.7, 13.9, 12.9, 11.9; HRMS m/z (ESI, M+Na + ) calcd
503.2979, found 503.2987.
For comparison the chemical shifts for (1) as reported by Moore are listed below.1
1H NMR (300 MHz, 1:1 C6D6:CDCI 3) (carbon on which the protons are located given in
parenthesis) 5 5.36 (OH on C3), 5.20 (C15), 5.15 (C9), 4.89 (C17), 4.51 (C13), 4.16 (C7), 4.0
(C5), 3.86 (C10), 2.39 (C2), 2.28 (C2), 2.19 (C16a), 1.97 (C1613), 1.62 (C23 methyl group at
C8), 1.54 (C6), 1.43 (C27 methyl group at C14), 1.30 (C6), 1.16 (C18, C19, C20, C21), 1.09
(C26 methyl group at C12), 1.03 (C24 methyl group at C10), 0.99 (C4), 0.84 (C25 methyl group
at C12), 0.80 (C22); 13C (75 MHz, Me 2SO-d 6) 6 124.4 (likely a typo and was meant to be 214.4
as observed by ourselves and by Smith) (C 11), 170.9 (C1), 136.1 (C8 or C14), 134.9 (C8 or
C14), 128.1 (C9), 123.6 (C15), 96.2 (C3), 77.3 (C13), 74.2 (C7), 73.8 (C17), 62.6 (C5), 53.0
(C12), 49.9 (C2), 43.5 (C4), 41.3 (C10), 38.2 (C6), 34.4 (C16), 31.8 (C20), 31.0 (C18), 24.4
(C19), 23.4 (C26 methyl group at C12), 22.0 (C21), 20.6 (C25 methyl group at C12), 16.7 (C24
methyl group at CIO), 13.9 (C22), 12.9 (C27 methyl group at C14), 11.9 (C23 methyl group at
C8).
120
Figure 2: (+)-acutiphycin (1)inCDCI 3
Synthetic
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CURRICULUM VITAE
Ryan Thomas McLeod Moslin
EDUCATION
Cambridge,MA
(MIT)
Massachusetts Institute of Technology
Ph.D. in Organic Chemistry, entered2001
"Nickel-CatalyzedReductive Coupling Reactions of 1,6-Enynes and the Total
Timothy F. Jamison, Research Advisor
Synthesis of (+)-Acutiphycin"
University of British Columbia
B.Sc. Honours Chemistry, 2001
(UBC)
Vancouver, BC
RESEARCH and PROFESSIONAL EXPERIENCE:
January2002 -present
Graduate Research Assistant - MIT
Sept 2001 - June 2003
Teaching Assistant - MIT
Sept 2000 - June 2001
Undergraduate Research Assistant - UBC
GregoryDake, Research Advisor
Summer 2000
Undergraduate Research Assistant - UBC
Edward Piers,Research Advisor
Undergraduate Research Assistant - UBC
Chris Orvig, Research Advisor
Summer 1999
AWARDS AND HONORS
Morse Travel Grant (MIT) - June 2004
Synlett Star Journal Award (MIT) - December 2001
Presidential Fellowship (MIT) - '01-'02 academicyear
NSERC Undergraduate Student Research Award - Summer 2000
Science Scholar (UBC) - exceptional academicperformance
Golden Key International Honour Society member
PUBLICATIONS and PRESENTATIONS
Moslin, Ryan M.; Miller-Moslin, Karen; Jamison, Timothy F. "Recent Advances in NickelCatalyzed Reductive Coupling Reactions of Alkynes," manuscript in preparation
Moslin, Ryan M.; Jamison, Timothy F. "Total Synthesis of (+)-Acutiphycin: Discovery of
Regioselective Nickel-Catalyzed Reductive Coupling Reactions Directed by a Remote
Alkene," manuscriptsubmitted forpublication.
Moslin, Ryan M.; Jamison, Timothy F. "Highly Convergent Total Synthesis of (+)Acutiphycin," J. Am. Chem. Soc. 2006, 128, 15106-15107.
199
Moslin, Ryan M.; Miller, Karen M.; Jamison, Timothy F. "Directing Effects of Tethered Alkenes
in Nickel-Catalyzed Couplings of 1,6-Enynes and Aldehydes," Tetrahedron 2006, 62,
7598-7610.
Moslin, Ryan M.; Jamison, Timothy F. "Mechanistic Implications of Nickel-Catalyzed
Reductive Coupling of Aldehydes and Chiral 1,6-Enynes," Org. Lett. 2006, 8, 455-458.
Moslin, Ryan T.; Jamison, Timothy F. "Towards the Synthesis of (+)-Acutiphycin,"
National Meeting, American Chemical Society, Philadelphia, PA, August 2004.
200
22 8 th